Dry powder formulations and methods of use

ABSTRACT

A respirable dry powder can include acetylsalicylic acid or a pharmaceutically acceptable salt thereof. The dry powder can include a mixture of: (i) dry particles have a volume median geometric diameter (VMGD) less than 5 μm; and (ii) dry particles have a volume median geometric diameter (VMGD) of about 15 μm or more.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/817,435, filed Apr. 30, 2013, which is incorporated by reference inits entirety.

FIELD

The subject technology relates generally to pulmonary delivery ofNSAIDs, such as aspirin. The subject technology also relates generallyto apparatuses and methods for delivery of substances, e.g., delivery ofmedication to the lungs using by inhalation for treating disease.

BACKGROUND

Pulmonary delivery of therapeutic agents can offer several advantagesover other modes of delivery. These advantages include rapid onset, theconvenience of patient self-administration, the potential for reduceddrug side-effects, ease of delivery by inhalation, the elimination ofneedles, and the like. Inhalation therapy is capable of providing a drugdelivery system that is easy to use in an inpatient or outpatientsetting, results in very rapid onset of drug action, and producesminimal side effects.

Metered dose inhalers (MDIs) are used to deliver therapeutic agents tothe respiratory tract. MDIs are generally suitable for administeringtherapeutic agents that can be formulated as solid respirable dryparticles in a volatile liquid under pressure. Opening of a valvereleases the suspension at relatively high velocity. The liquid thenvolatilizes, leaving behind a fast-moving aerosol of dry particles thatcontain the therapeutic agent.

Liquid aerosol delivery is one of the oldest forms of pulmonary drugdelivery. Typically, liquid aerosols are created by an air jetnebulizer, which releases compressed air from a small orifice at highvelocity, resulting in low pressure at the exit region due to theBernoulli effect. See, e.g., U.S. Pat. No. 5,511,726. The low pressureis used to draw the fluid to be aerosolized out of a second tube. Thisfluid breaks into small droplets as it accelerates in the air stream.Disadvantages of this standard nebulizer design include relatively largeprimary liquid aerosol droplet size often requiring impaction of theprimary droplet onto a baffle to generate secondary splash droplets ofrespirable sizes, lack of liquid aerosol droplet size uniformity,significant recirculation of the bulk drug solution, and low densitiesof small respirable liquid aerosol droplets in the inhaled air. Inaddition, a particular compound of interest may not be compatible withsolvents typically used in nebulizer delivery systems.

Ultrasonic nebulizers use flat or concave piezoelectric disks submergedbelow a liquid reservoir to resonate the surface of the liquidreservoir, forming a liquid cone which sheds aerosol particles from itssurface (U.S. 2006/0249144 and U.S. Pat. No. 5,551,416). Since noairflow is required in the aerosolization process, high aerosolconcentrations can be achieved, however the piezoelectric components arerelatively expensive to produce and are inefficient at aerosolizingsuspensions, requiring active drug to be dissolved at low concentrationsin water or saline solutions. Newer liquid aerosol technologies involvegenerating smaller and more uniform liquid respirable dry particles bypassing the liquid to be aerosolized through micron-sized holes. See,e.g., U.S. Pat. No. 6,131,570; U.S. Pat. No. 5,724,957; and U.S. Pat.No. 6,098,620. Disadvantages of this technique include relativelyexpensive piezoelectric and fine mesh components as well as fouling ofthe holes from residual salts and from solid suspensions.

Dry powder inhalation has historically relied on lactose blending toallow for the dosing of particles that are small enough to be inhaled,but aren't dispersible enough on their own. This process is known to beinefficient and to not work for some drugs. Several groups have tried toimprove on these shortcomings by developing dry powder inhaler (DPI)formulations that are respirable and dispersible and thus do not requirelactose blending. Dry powder formulations for inhalation therapy aredescribed in U.S. Pat. No. 5,993,805 to Sutton et al.; U.S. Pat. No.6,921,6527 to Platz et al.; WO 0000176 to Robinson et al.; WO 9916419 toTarara et al.; WO 0000215 to Bot et al; U.S. Pat. No. 5,855,913 to Haneset al.; and U.S. Pat. Nos. 6,136,295 and 5,874,064 to Edwards et al.

Broad clinical application of dry powder inhalation delivery has beenlimited by difficulties in generating dry powders of appropriateparticle size, particle density, and dispersibility, in keeping the drypowder stored in a dry state, and in developing a convenient, hand-helddevice that effectively disperses the respirable dry particles to beinhaled in air. In addition, the particle size of dry powders forinhalation delivery is inherently limited by the fact that smallerrespirable dry particles are harder to disperse in air. Dry powderformulations, while offering advantages over cumbersome liquid dosageforms and propellant-driven formulations, are prone to aggregation andlow flowability, which considerably diminish dispersibility and theefficiency of dry powder-based inhalation therapies. For example,interparticular Van der Waals interactions and capillary condensationeffects are known to contribute to aggregation of dry particles. Hickey,A. et al., “Factors Influencing the Dispersion of Dry Powders asAerosols”, Pharmaceutical Technology, August, 1994.

To overcome interparticle adhesive forces, Batycky et al. in U.S. Pat.No. 7,182,961 teach production of so called “aerodynamically lightrespirable particles,” which have a volume median geometric diameter(VMGD) of greater than 5 microns (μm) as measured using a laserdiffraction instrument such as HELOS (manufactured by Sympatec,Princeton, N.J.). See Batycky et al., column 7, lines 42-65. Anotherapproach to improve dispersibility of respirable particles of averageparticle size of less than 10 μm, involves the addition of a watersoluble polypeptide or addition of suitable excipients (including aminoacid excipients such as leucine) in an amount of 50% to 99.9% by weightof the total composition. Eljamal et al., U.S. Pat. No. 6,582,729,column 4, lines 12-19 and column 5, line 55 to column 6, line 31.However, this approach reduces the amount of active agent that can bedelivered using a fixed amount of powder. Therefore, an increased amountof dry powder is required to achieve the intended therapeutic results,for example, multiple inhalations and/or frequent administration may berequired. Still other approaches involve the use of devices that applymechanical forces, such as pressure from compressed gasses, to the smallparticles to disrupt interparticular adhesion during or just prior toadministration. See, e.g., U.S. Pat. No. 7,601,336 to Lewis et al., U.S.Pat. No. 6,737,044 to Dickinson et al., U.S. Pat. No. 6,546,928 toAshurst et al., or U.S. Pat. Applications 20090208582 to Johnston et al.

A further limitation that is shared by each of the above methods is thatthe aerosols produced typically include substantial quantities of inertcarriers, solvents, emulsifiers, propellants, and other non-drugmaterial. In general, the large quantities of non-drug material arerequired for effective formation of respirable dry particles smallenough for alveolar delivery (e.g. less than 5 μm and preferably lessthan 3 μm). However, these amounts of non-drug material also serve toreduce the purity and amount of active drug substance that can bedelivered. Thus, these methods remain substantially incapable ofintroducing large active drug dosages accurately to a patient forsystemic delivery.

A thromboembolic event, such as myocardial infarction, deep venousthrombosis, pulmonary embolism, thrombotic stroke, etc., can presentwith certain symptoms that allow a patient or clinician to provide aninitial therapy or treatment for the event. In some situations, an 81mg, low dose, or baby aspirin or a regular aspirin (330 mg) may beorally administered in order to provide an initial treatment for thepatient.

There remains a need for providing novel formulations of non-steroidalanti-inflammatory drugs (“NSAIDs”), such as aspirin, that are suitablefor pulmonary delivery.

SUMMARY

The subject technology generally relates to respirable dry powderscomprising dry particles that comprise an NSAID, such as acetylsalicylicacid, as an active ingredient. The respirable dry particles may be largeor small, e.g., a geometric diameter (VMGD) between 0.5 μm and 30 μm.Alternatively or in addition, the respirable dry powders can have a massmedian aerodynamic diameter (MMAD) of about 20 μm or less. Optionally,the MMAD of the particles may be between 0.5 and 10 μm, more preferablybetween 1 and 10 μm.

The dry powders may also comprise a mixture of particles of large sizes(e.g., 20-30 μm) and of small sizes (e.g., 5 μm or less). This way,smaller particles could reach the lower respiratory tract and largerparticles would be captured in the upper respiratory tract.

The respirable dry powder compositions can include a pharmaceuticallyacceptable excipient, such as leucine, sodium citrate, maltodextrin ormannitol, which may be present in an amount of about 5% to about 90% orby weight. The inclusion of an excipient is optional.

In some embodiments, the NSAID, such as acetylsalicylic acid, isprovided in a dry powder formulation comprising a mixture of particlesof various sizes, for example, a mixture of (i) particles having a meangeometric diameter (VMGD) and/or mass median aerodynamic diameter (MMAD)of 5 μm or less, and (ii) particles having a mean geometric diameter(VMGD) and/or mass median aerodynamic diameter (MMAD) of 15 μm orgreater. In some embodiments the composition may further include apharmaceutically acceptable excipient. In other embodiments, thecomposition is free or substantially free of excipient. In certainembodiments, the composition is free or substantially free ofanti-aggregation excipient.

The subject technology also relates to a respirable dry powder or dryparticle, as described herein, for use in therapy (e.g., treatment,prophylaxis, or diagnosis). The subject technology also relates to theuse of a respirable dry particle or dry powder, as described herein, foruse in treatment (including prophylactic treatment, such as preventionor reducing the risk) of a cardiovascular disease (such as thrombosis)as described herein, and in the manufacture of a medicament for thetreatment, prophylaxis or diagnosis of a cardiovascular disease (such asthrombosis) as described herein.

The subject technology also provides a drug delivery system for treating(including prophylactic treatment or reducing the risk of) acardiovascular disease (such as thrombosis), the system comprising: atherapeutically effective dose of an NSAID (such as acetylsalicylicacid) in dry powder form; a dry powder inhaler, the dry powder inhalercomprising a mouthpiece, a reservoir for receiving the dose of the NSAID(such as acetylsalicylic acid), and an actuation member for makingavailable the dose of the acetylsalicylic acid for inhalation by thepatient through the mouthpiece. Preferably, the dose of the NSAID (suchas acetylsalicylic acid) is about 40 mg or less, more preferably, 30 mgor less.

Another aspect of at least one embodiment disclosed herein includes therecognition of a need for improved apparatuses and methods for deliveryof drugs for treating disease that utilize a dosage that is effective toreduce a risk of a thromboembolic event in a patient, lower thantraditional dosages, and administered using a more direct deliverymechanism to the systemic blood stream.

Additional features and advantages of the subject technology will be setforth in the description below, and in part will be apparent from thedescription, or may be learned by practice of the subject technology.The advantages of the subject technology will be realized and attainedby the structure particularly pointed out in the written description andclaims hereof as well as the appended drawings.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory and areintended to provide further explanation of the subject technology asclaimed.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are included to provide furtherunderstanding of the subject technology and are incorporated in andconstitute a part of this specification, illustrate aspects of thesubject technology and together with the description serve to explainthe principles of the subject technology.

FIG. 1 is a schematic view of a patient using a dry powder inhaler, inaccordance with some implementations of the methods and systemsdisclosed herein.

FIGS. 2A-F illustrate usages and a configuration of a dry powderinhaler, according to some embodiments.

DETAILED DESCRIPTION

In the following detailed description, numerous specific details are setforth to provide a full understanding of the subject technology. It willbe apparent, however, to one ordinarily skilled in the art that thesubject technology may be practiced without some of these specificdetails. In other instances, well-known structures and techniques havenot been shown in detail so as not to obscure the subject technology.

1. Introduction

Thromboembolic Symptoms and Events

A thromboembolic event, such as myocardial infarction, deep venousthrombosis, pulmonary embolism, thrombotic stroke, etc., can presentwith certain symptoms that allow a patient or clinician to provide aninitial therapy or treatment for the event. In some situations, an 81mg, low dose, or baby aspirin or a regular aspirin (330 mg) may beorally administered in order to provide an initial treatment for thepatient.

According to some embodiments disclosed herein is the realization thatthis treatment may not act as quickly as necessary to provide asufficient therapeutic effect and therefore, may lead to a lesspreferred outcome. Thus, in some embodiments, a drug delivery system andrelated methods are disclosed that provide an accelerated and moreefficient pathway and treatment for reducing the risk of athromboembolic event and/or providing treatment for a thromboembolicevent. For example, some embodiments provide systems and methods ofadministering a non-steroidal anti-inflammatory drug (“NSAID”) byinhalation, such as by a dry powder inhaler (“DPI”) or a metered doseinhaler (“MDI”).

Delivery Mechanisms for Drugs

Drugs can be administered orally in different ways, such as liquids,capsules, tablets, or chewable tablets. The oral route is used mostoften because it is the most convenient, safest, and least expensive.However, oral drug delivery has limitations because of the way a drugtypically moves through the digestive tract.

For example, when a drug is administered orally, it is absorbed in themouth, stomach, and the small intestine. Before the drug enters thebloodstream, it must pass through the intestinal wall and travels to theliver. While passing through the intestinal wall and liver, the drug ismetabolized, which can decrease the amount of the drug that actuallyreaches the bloodstream. The metabolism of the drug reduces thebioavailability of the drug and is often termed the “first pass effect.”The fraction of the drug lost during due to the first pass effect isgenerally determined by absorption in the liver and gut wall, andgastrointestinal lumen enzymes, gut wall enzymes, bacterial enzymes, andhepatic (liver) enzymes.

Generally, the first pass effect on aspirin significantly reduces thebioavailability of the administered dosage. For example, due to theacidic conditions in the stomach, aspirin is absorbed in the stomach andthe upper small intestine. After being absorbed, aspirin is metabolizedto acetic acid and salicylate. When taken orally, generally only aboutone to two-thirds of the dose of aspirin is bioavailable due to thefirst pass effect.

For example, in Iwamoto K., GASTROINTESTINAL AND HEPATIC FIRST-PASSMETABOLISM OF ASPIRIN IN RATS, J Pharm Pharmacol. 1982 March; 34(3), pp.176-80, the study examines the absorption of aspirin in four malesubjects following an oral solution of 650 mg. As stated in the studyreport, “the absorption process appeared to follow first-order kinetics,with a half-life ranging from 4.5 to 16.0 min. between subjects.Comparison of the area under the aspirin plasma concentration-time curvefollowing intravenous and oral routes indicated that only 68% of thedose reached the peripheral circulation intact.”

Applicant has determined that even drugs that are administered byinhalation undergo a first pass effect. For drug administration byinhalation, smaller particles proceed via a nasal route, down thewindpipe (trachea) and into the lungs. The size of the particles can bedeterminative of the overall efficacy of the treatment. Once inside thelungs, these particles are absorbed into the bloodstream.

Few drugs are administered by inhalation because the dosage of aninhaled drug, as well as the delivery timing, can often be difficult tomeasure. Usually, this method is used to administer drugs that actspecifically on the lungs, such as aerosolized antiasthmatic drugs inmetered-dose containers, and to administer gases used for generalanesthesia.

Pharmacokinetics of Aspirin

Aspirin is the acetylated form of salicylic acid, and the activechemical in aspirin is called acetylsalicylic acid (ASA). Aspirin isused by millions of people to achieve desirable effects, and by manypeople, baby aspirin is often used daily. The principal effect ofaspirin is to impair the function of cyclooxygenase enzymes(specifically, COX1 and COX2 enzymes).

By inhibiting COX1, aspirin can irreversibly inhibit plateletaggregation, which decreases the risk of blood clots. Additionally, theimpairment of the COX2 enzyme can reduce inflammation, stiffness, andpain in the body by inhibiting prostaglandins and thromboxanes. As such,individuals at high risk for heart attack, stroke, or with inflammationoften take aspirin to address symptoms and effects of these conditions.As noted, aspirin can effectively reduce the likelihood of suchmyocardial events and reduce pain and inflammation with a dose as smallas a baby aspirin. However, due at least in part to its inhibition ofCOX1, aspirin can increase the risk of bleeding and cause damage toorgans such as the stomach and intestines, which can be painful.

Dry Powder Inhaler Technology

As stated above, the oral delivery of aspirin may create a risk ofdamage to the stomach wall leading to pain, indigestion and a high riskof bleeding. Further, according to at least one of the aspects ofembodiments disclosed herein is the realization that it is oftendifficult to orally administer a drug during emergency situations thatmay implicate or result in a thromboembolic event. For example, thepatient may be experiencing vomiting or otherwise be unable to take thedrug orally. Additionally, oral administration of a drug may beundesirable because the drug does not reach the systemic blood streamimmediately, thus delaying the important effects of the drug. Even so,due to the first pass effect in the liver and gut, the amount of drugreaching systemic circulation is much less than that administered.Therefore, according to aspects of various embodiments disclosed hereinis the realization that an alternative route of administration couldavoid these unwanted side-effects.

Various embodiments disclosed herein reflect the novel realization thatdelivery of a drug by inhalation in the early stages of an emergencysituation can provide a fast-acting, effective form of preliminarytreatment of certain medical conditions. For example, in someembodiments, upon receiving a complaint of a symptom of a seriousthromboembolic event, a patient can be administered, by DPI, atherapeutic amount of a NSAID. The NSAID can address problems associatedwith or provide an initial treatment for the medical condition.

However, dry powder inhalation of drugs has generally been limited bycough, to dosages of less than a milligram. Recent developments inparticle engineering, in particular the development of PulmoSphere™technology, have enabled the delivery of a larger amount of dry powderto the lungs in a single actuation. See David E. Geller, M. D., et al.,DEVELOPMENT OF AN INHALED DRY-POWDER FORMULATION OF TOBRAMYCIN USINGPULMOSPHERE™ TECHNOLOGY, J Aerosol Med Pulm Drug Deliv. 2011 August;24(4), pp. 175-82. In this publication, a dose of 112 mg tobramycin (infour capsules) was effectively delivered via PulmoSpheres™.

In accordance with some embodiments is the realization that the bodyincludes various particle filters that limit the efficacy of inhaleddrugs. For example, the oropharynx tends to prevent passage of particleshaving a diameter greater than 5 μm. However, in order to reach thealveoli, particles must have a size from about 1 μm to about 5 μm.Accordingly, some embodiments herein disclose the preparation and use ofinhalable aspirin using technology similar to PulmoSpheres™ to produceparticles with a median geometric diameter of from about 1 μm to about 5μm, and in some embodiments, from about 1.7 μm to about 2.7 μm.

There has been no single dose use of aspirin by dry powder inhaler toreplace the traditional daily use of a NSAID (such as a baby aspirin) oremergency use of a NSAID as preventative care for symptoms of athromboembolic event. Accordingly, some embodiments disclosed hereinprovide methods for administering a NSAID by dry powder inhalation in anamount less than the dosage of a baby aspirin (e.g., less than 81 mg).

Therefore, in some embodiments, a method for treating disease, e.g., byreducing the risk of a thromboembolic event, can be provided, whichcomprises administering a NSAID, such as a salicylate, by a DPI or MDI.For example, the method can comprise administering acetylsalicylic acidby a DPI or MDI. The administered dosage can be less than 25 mg ofacetylsalicylic acid. Further, the administered dosage can be less than20 mg of acetylsalicylic acid. The administered dosage can be less than15 mg of acetylsalicylic acid. The administered dosage can also be lessthan 12 mg of acetylsalicylic acid. The administered dosage can be lessthan 10 mg of acetylsalicylic acid. Furthermore, the administered dosagecan be less than 8 mg of acetylsalicylic acid. The administered dosagecan be less than 5 mg of acetylsalicylic acid. In some embodiments, theadministered dosage can be less than 2 mg of acetylsalicylic acid.

For example, according to some embodiments, the dosage can be from about2 mg to about 30 mg of acetylsalicylic acid. In some embodiments, thedosage can be from about 4 mg to about 25 mg of acetylsalicylic acid.The dosage can be from about 6 mg to about 20 mg of acetylsalicylicacid. Further, in some embodiments, the dosage can be from about 8 mg toabout 15 mg of acetylsalicylic acid. Further, in some embodiments, thedosage can be from about 10 mg to about 13 mg of acetylsalicylic acid.For example, in some embodiments, the dosage can be about 1 mg, 2 mg, 3mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14mg, 15 mg, 16 mg, 17 mg, 18 mg, 19 mg, or 20 mg of acetylsalicylic acid.

Additionally, the dose of acetylsalicylic acid can be less than about 80mg. In some embodiments, the dose of acetylsalicylic acid can be fromabout 1 mg to about 75 mg. In some embodiments, the dose ofacetylsalicylic acid can be from about 2 mg to about 60 mg. In someembodiments, the dose of acetylsalicylic acid can be from about 5 mg toabout 40 mg. In some embodiments, the dose of acetylsalicylic acid canbe from about 10 mg to about 30 mg. In some embodiments, the dose ofacetylsalicylic acid can be from about 12 mg to about 25 mg. In someembodiments, the dose of acetylsalicylic acid can be from about 15 mg toabout 20 mg.

In accordance with some embodiments, such dosages can provide abioequivalent dosage when compared to typical dosages of 81 mg to about325 mg, while demonstrating few negative side effects.

Thus, in some embodiments, a NSAID, such as aspirin, can be administeredby DPI or MDI in a single dose that is much less than a traditional oraldose of aspirin, which can provide a bioequivalent equivalent treatmentwhile tending to avoid the negative side effects associated with someNSAIDs, such as aspirin. Further, systems of administering suchtreatments are also provided.

The DPI or MDI can have a mouthpiece and an actuation member for makingavailable the NSAID for inhalation by a patient to reduce the risk ofthe thromboembolic event.

For example, according to some embodiments, a method of reducing therisk of a thromboembolic event is provided and can compriseadministering a dose of a non-steroidal anti-inflammatory drug by a drypowder inhaler. The dose can be effective to reduce a risk of athromboembolic event in a patient. The dry powder inhaler can have amouthpiece and an actuation member for making available the dose of thenon-steroidal anti-inflammatory drug for inhalation by the patient toreduce the risk of the thromboembolic event.

A drug delivery system can also be provided according to someembodiments, for treating a disease, for example, by reducing the riskof a thromboembolic event. The system can comprise a dose of anon-steroidal anti-inflammatory drug in powder form. The dose can beeffective to reduce a risk of a thromboembolic event in a patient. Thesystem can also comprise a dry powder inhaler. The dry powder inhalercan have a mouthpiece, a reservoir for receiving the dose of thenon-steroidal anti-inflammatory drug, and an actuation member for makingavailable the dose of the non-steroidal anti-inflammatory drug forinhalation by the patient through the mouthpiece.

In some embodiments, the thromboembolic event comprises at least one ofmyocardial infarction, deep venous thrombosis, pulmonary embolism, orthrombotic stroke. The dose of the non-steroidal anti-inflammatory drugcan be administered as a preliminary treatment in response to a symptomof a thromboembolic event. The non-steroidal anti-inflammatory drug cancomprise aspirin. Further, the dose of the non-steroidalanti-inflammatory drug can be administered in a single dose.

2. Definitions

The term “about”, as used here, refers to +/−5% of a value.

The term “dry powder” as used herein refers to a composition containsfinely dispersed respirable dry particles that are capable of beingdispersed in an inhalation device and subsequently inhaled by a subject.Such dry powder or dry particle may contain up to about 15% water orother solvent, or be substantially free of water or other solvent, or beanhydrous.

The term “dry particles” as used herein refers to respirable particlesthat may contain up to about 15% water or other solvent, or besubstantially free of water or other solvent, or be anhydrous.

The term “respirable” as used herein refers to dry particles or drypowders that are suitable for delivery to the respiratory tract (e.g.,pulmonary delivery) in a subject by inhalation. Respirable dry powdersor dry particles have a mass median aerodynamic diameter (MMAD) of lessthan about 10 μm, preferably about 5 μm or less.

As used herein, the terms “administration” or “administering” ofrespirable dry particles refers to introducing respirable dry particlesto the respiratory tract of a subject.

The term “dispersible” is a term of art that describes thecharacteristic of a dry powder or dry particles to be dispelled into arespirable aerosol. Dispersibility of a dry powder or dry particles isexpressed herein as the quotient of the volume median geometric diameter(VMGD) measured at a dispersion (i.e., regulator) pressure of 1 bardivided by the VMGD measured at a dispersion (i.e., regulator) pressureof 4 bar, or VMGD at 0.5 bar divided by the VMGD at 4 bar as measured byHELOS/RODOS. These quotients are referred to herein as “¼ bar,” and“0.5/4 bar,” respectively, and dispersibility correlates with a lowquotient. For example, ¼ bar refers to the VMGD of respirable dryparticles or powders emitted from the orifice of a RODOS dry powderdisperser (or equivalent technique) at about 1 bar, as measured by aHELOS or other laser diffraction system, divided the VMGD of the samerespirable dry particles or powders measured at 4 bar by HELOS/RODOS.Thus, a highly dispersible dry powder or dry particles will have a ¼ baror 0.5/4 bar ratio that is close to 1.0. Highly dispersible powders havea low tendency to agglomerate, aggregate or clump together and/or, ifagglomerated, aggregated or clumped together, are easily dispersed orde-agglomerated as they emit from an inhaler and are breathed in by thesubject. Dispersibility can also be assessed by measuring the sizeemitted from an inhaler as a function of flowrate.

As used herein, the term “emitted dose” or “ED” refers to an indicationof the delivery of a drug formulation from a suitable inhaler deviceafter a firing or dispersion event. More specifically, for dry powderformulations, the ED is a measure of the percentage of powder that isdrawn out of a unit dose package and that exits the mouthpiece of aninhaler device. The ED is defined as the ratio of the dose delivered byan inhaler device to the nominal dose (i.e., the mass of powder per unitdose placed into a suitable inhaler device prior to firing). The ED isan experimentally-measured parameter, and can be determined using themethod of USP Section 601 Aerosols, Metered-Dose Inhalers and Dry PowderInhalers, Delivered-Dose Uniformity, Sampling the Delivered Dose fromDry Powder Inhalers, United States Pharmacopeia Convention, Rockville,Md., 13^(th) Revision, 222-225, 2007. This method utilizes an in vitrodevice set up to mimic patient dosing.

The terms “FPF(<5.6),” “FPF(<5.6 μm),” and “fine particle fraction ofless than 5.6 μm” as used herein, refer to the fraction of a sample ofdry particles that have an aerodynamic diameter of less than 5.6 μm. Forexample, FPF(<5.6) can be determined by dividing the mass of respirabledry particles deposited on the stage one and on the collection filter ofa two-stage collapsed Andersen Cascade Impactor (ACI) by the mass ofrespirable dry particles weighed into a capsule for delivery to theinstrument. This parameter may also be identified as “FPF_TD(<5.6),”where TD means total dose. A similar measurement can be conducted usingan eight-stage ACL The eight-stage ACI cutoffs are different at thestandard 60 L/min flowrate, but the FPF_TD(<5.6) can be extrapolatedfrom the eight-stage complete data set. The eight-stage ACI result canalso be calculated by the USP method of using the dose collected in theACI instead of what was in the capsule to determine FPF.

The terms “FPF(<3.4),” “FPF(<3.4 μm),” and “fine particle fraction ofless than 3.4 μm” as used herein, refer to the fraction of a mass ofrespirable dry particles that have an aerodynamic diameter of less than3.4 For example, FPF(<3.4) can be determined by dividing the mass ofrespirable dry particles deposited on the collection filter of atwo-stage collapsed ACI by the total mass of respirable dry particlesweighed into a capsule for delivery to the instrument. This parametermay also be identified as “FPF_TD(<3.4),” where TD means total dose. Asimilar measurement can be conducted using an eight-stage ACI. Theeight-stage ACI result can also be calculated by the USP method of usingthe dose collected in the ACI instead of what was in the capsule todetermine FPF.

The terms “FPF(<5.0),” “FPF(<5.0 μm),” and “fine particle fraction ofless than 5.0 μm” as used herein, refer to the fraction of a mass ofrespirable dry particles that have an aerodynamic diameter of less than5.0 For example, FPF(<5.0) can be determined by using an eight-stage ACIat the standard 60 L/min flowrate by extrapolating from the eight-stagecomplete data set. This parameter may also be identified as“FPF_TD(<5.0),” where TD means total dose.

The term “nanoparticles” refers to particles that have a singlecrystallite grain between about 1 nm to about 900 nm, preferably betweenabout 5 nm to about 500 nm. Individual grains can agglomerate intoclusters/agglomerates.

The term “excipient” refers to a pharmacologically inactive substanceformulated with the active ingredient (“API”) of a medication.

A phrase such as “an aspect” does not imply that such aspect isessential to the subject technology or that such aspect applies to allconfigurations of the subject technology. A disclosure relating to anaspect may apply to all configurations, or one or more configurations.An aspect may provide one or more examples of the disclosure. A phrasesuch as “an aspect” may refer to one or more aspects and vice versa. Aphrase such as “an embodiment” does not imply that such embodiment isessential to the subject technology or that such embodiment applies toall configurations of the subject technology. A disclosure relating toan embodiment may apply to all embodiments, or one or more embodiments.An embodiment may provide one or more examples of the disclosure. Aphrase such “an embodiment” may refer to one or more embodiments andvice versa. A phrase such as “a configuration” does not imply that suchconfiguration is essential to the subject technology or that suchconfiguration applies to all configurations of the subject technology. Adisclosure relating to a configuration may apply to all configurations,or one or more configurations. A configuration may provide one or moreexamples of the disclosure. A phrase such as “a configuration” may referto one or more configurations and vice versa.

3. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

NSAIDs, such as aspirin, can provide various beneficial effects andcontribute to reducing the risk of a cardiovascular disease (such asthrombosis). However, the use of NSAIDs, such as aspirin, in a clinicalsetting has traditionally been limited to oral administration. Oraladministration of aspirin, for example, can result in the loss orinactivation of approximately ⅔ of the oral dosage due to the first passeffect in the gut and liver. While one third of the dosage reaches thesystemic blood stream and provides the desired effect, the negative sideeffects created by the full dosage often deter patients from usingaspirin on a regular or daily basis.

Further, in many situations, such as in emergencies, oral administrationof NSAIDs, such as aspirin, may be inappropriate because it may take toolong to be effective. According to at least one aspect of someembodiments disclosed herein is the realization that an alternativeadministration method and systems can be implemented that utilize alower dosage and provide a more direct delivery mechanism to thesystemic blood stream. Thus, some embodiments disclosed herein allow forthe beneficial effects of NSAIDs, such as aspirin, to be achieved on aregular basis and in emergency situations, while minimizing previousdrawbacks associated with the use of NSAIDs.

Various studies have determined that aspirin has a significant effect onreducing the risk of myocardial infarction. However, these studiespresented inconclusive data on strokes, pulmonary embolism, or deepvenous thrombosis. These studies have used aspirin dosages of 325 mg.However, these studies have based their findings on oral administrationof aspirin and have not suggested DPI or MDI pathways, which areprovided in some embodiments disclosed herein. Further, theadministration of aspirin has negative side effects, such assignificantly increasing major gastrointestinal and extracranial bleedsby over 50%. This has led some to argue that for preventative treatment,aspirin is of uncertain net value.

Further studies have tested whether the benefits of aspirin could beobtained at low dosages, such as that of baby aspirin (i.e., 81 mg). TheSwedish Aspirin Low-dose Trial (SALT) found that a low dose (75 mg/day)of aspirin significantly reduces the risk of stroke or death in patientswith cerebrovascular ischaemic events. However, the study also reportedgastrointestinal side-effects that included a significant excess ofbleeding episodes. A Danish study found that patients receiving aspirinas an antithrombotic agent achieved satisfactory platelet inhibitionwith 50 mg/day, while the remainder of the patients needed over 50mg/day. Furthermore, a Dutch TIA Study concluded that aspirin at anydose above 30 mg daily prevents 13% of vascular events, and that thereis a need for more efficacious drugs. However, no study or teaching hasbeen provided regarding the administration of aspirin by DPI or MDI atvery low doses.

Although inhaled dry powder formulations of aspirin have been developed,reports have stated that the formulation was not clinically feasiblebecause it is difficult to meet the high dosage requirements of aspirin(˜80 mg/day for low-dose prevention of coronary events and stroke, andat least 300 mg/day for pain or fever relief) via pulmonary delivery ofdry powders.

In addition, these reports recognize that adverse effects of dry powderon the lungs, such as coughing, cannot be avoided unless the doses areless than a few tenths of a milligram in a single breath. Thus, priorteachings suggest that higher dosage requirements of aspirin would beimpossible to meet using DPI. Finally, some have taught that there is ahigher incidence of aspirin intolerance in asthmatic patients whenaspirin is delivered by inhalation than orally.

In yet another study, the authors noted that use of nanoparticulatedrugs for dry powder inhaler (DPI) delivery is not straightforward.Direct inhalation of nanoparticulate drugs was infeasible due to theirsmall size. The nanometer size leads to the nanoparticulate drugs beingpredominantly exhaled from the lungs, without any deposition in thelungs taking place. Moreover, a severe aggregation problem arising fromthe small size makes their physical handling difficult for DPI delivery.Accordingly, “large hollow carrier particles” of nanoparticulate drugshas been developed for pulmonary delivery of some drugs. See Hadinoto etal., Drug Release Study Of Large Hollow Nanoparticulate AggregatesCarrier Particles For Pulmonary Delivery, International Journal ofPharmaceutics 341 (2007) 195-20.

In the Hadinoto study, the authors used aspirin as a model for “lowlywater-soluble” drugs. The authors acknowledged that “with regard to theaspirin, the nanoparticulate polymer delivery method is not the mostsuitable method of delivery due to the high dosage requirement ofaspirin (˜300 mg/day),” and overall, the aim of the study was toidentify key facets in the formulation of the large hollownanoparticulate aggregates. See id.

In some embodiments of the inventions disclosed herein, methods andsystems are provided for treating (including prophylactic treatment orreducing the risk of) a disease, for example, treating a cardiovasculardisease (such as thrombosis) by administration of a very low amount of aNSAID, such as a low dose of aspirin, by DPI. The dose can be much lessthan that of a baby aspirin (e.g., less than 81 mg). The administereddosage can be less than 25 mg of acetylsalicylic acid. Further, theadministered dosage can be less than 20 mg of acetylsalicylic acid. Theadministered dosage can be less than 15 mg of acetylsalicylic acid. Theadministered dosage can also be less than 12 mg of acetylsalicylic acid.The administered dosage can be less than 10 mg of acetylsalicylic acid.Furthermore, the administered dosage can be less than 8 mg ofacetylsalicylic acid. The administered dosage can be less than 5 mg ofacetylsalicylic acid. In some embodiments, the administered dosage canbe less than 2 mg of acetylsalicylic acid.

For example, according to some embodiments, the dosage can be from about2 mg to about 30 mg. In some embodiments, the dosage can be from about 4mg to about 25 mg of acetylsalicylic acid. The dosage can be from about6 mg to about 20 mg of acetylsalicylic acid. Further, in someembodiments, the dosage can be from about 8 mg to about 15 mg ofacetylsalicylic acid. Further, in some embodiments, the dosage can befrom about 10 mg to about 13 mg of acetylsalicylic acid. For example, insome embodiments, the dosage can be about 1 mg, 2 mg, 3 mg, 4 mg, 5 mg,6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 16 mg,17 mg, 18 mg, 19 mg, or 20 mg of acetylsalicylic acid.

Additionally, the dose of acetylsalicylic acid can be less than about 80mg. In some embodiments, the dose of acetylsalicylic acid can be fromabout 1 mg to about 75 mg. In some embodiments, the dose ofacetylsalicylic acid can be from about 2 mg to about 60 mg. In someembodiments, the dose of acetylsalicylic acid can be from about 5 mg toabout 40 mg. In some embodiments, the dose of acetylsalicylic acid canbe from about 10 mg to about 30 mg. In some embodiments, the dose ofacetylsalicylic acid can be from about 12 mg to about 25 mg. In someembodiments, the dose of acetylsalicylic acid can be from about 15 mg toabout 20 mg.

Such dosages can provide a bioequivalent dosage when compared to typicaldosages of 81 mg to about 325 mg, while demonstrating few negative sideeffects.

In some embodiments, NSAIDs can be used in various methods and systems.In some embodiments, NSAIDs can include salicylates, i.e., the salts andesters of salicylic acid, which have anti-platelet action. Further,NSAIDs can also include one or more of the following:

Aspirin (Aspirin is a brand name; the chemical is called acetylsalicylicacid) Celecoxib (Celebrex) Dexdetoprofen (Keral) Diclofenac (Voltaren,Cataflam, Voltaren-XR) Diflunisal (Dolobid) Etodolac (Lodine, Lodine XL)Etoricoxib (Algix) Fenoprofen (Fenopron, Nalfron) Firocoxib (Equioxx,Previcox) Flurbiprofen (Urbifen, Ansaid, Flurwood, Froben) Ibuprofen(Advil, Brufen, Motrin, Nurofen, Medipren, Nuprin) Indomethacin(Indocin, Indocin SR, Indocin IV) Ketoprofen (Actron, Orudis, Oruvail,Ketoflam) Ketorolac (Toradol, Sprix, Toradol IV/IM, Toradol IM)Licofelone (under development) Lornoxicam (Xefo) Loxoprofen (Loxonin,Loxomac, Oxeno) Lumiracoxib (Prexige) Meclofenamic acid (Meclomen)Mefenamic acid (Ponstel) Meloxicam (Movalis, Melox, Recoxa, Mobic)Nabumetone (Relafen) Naproxen (Aleve, Anaprox, Midol Extended Relief,Naprosyn, Naprelan) Nimesulide (Sulide, Nimalox, Mesulid) Oxaporozin(Daypro, Dayrun, Duraprox) Parecoxib (Dynastat) Piroxicam (Feldene)Rofecoxib (Vioxx, Ceoxx, Ceeoxx) Salsalate (Mono-Gesic, Salflex,Disalcid, Salsitab) Sulindac (Clinoril) Tenoxicam (Mobiflex) Tolfenamicacid (Clotam Rapid, Tufnil) Valdecoxib (Bextra)

Other alternatives can also be used instead of a NSAID in some methodsor systems disclosed herein. Such alternatives include as Plavix(clopidogrel), COX-2 inhibitors, other remedies such as Nattokinase (anenzyme (EC 3.4.21.62, extracted and purified from a Japanese food callednattō). Further, other drugs that provide different beneficial effects,such as being effective to reduce a risk of a cardiovascular disease(such as thrombosis) in a patient, can also be used in some embodiments.Thus, the discussion of methods and systems shall apply generally tothese various alternatives, although for discussion purposes, thepresent disclosure often refers to aspirin. It is contemplated that themethods, effects, pharmacokinetic data, and other considerationsrelating to aspirin can be equally applied to other NSAIDs, according tosome embodiments.

4. Dry Powders and Dry Particles

The subject technology relates to respirable dry powders and dryparticles that comprise an NSAID, such as acetylsalicylic acid, as anactive ingredient.

In one aspect, the dry particles of the subject technology are small,and preferably are dispersible. The size of the dry particles can beexpressed in a variety of ways that are conventional in the art, suchas, fine particle fraction (FPF), volumetric median geometric diameter(VMGD), or mass median aerodynamic diameter (MMAD).

In certain embodiments, the dry particles of the subject technology aresmall and preferably dispersible. For example, the dry particles of thesubject technology may have a VMGD as measured by HELOS/RODOS at 1.0 barof about 10 μm or less (e.g., about 0.1 μm to about 10 μm). Preferably,the dry particles of the subject technology have an VMGD of about 9 μmor less (e.g., about 0.1 μm to about 9 about 8 μm or less (e.g., about0.1 μm to about 8 μm), about 7 μm or less (e.g., about 0.1 μm to about 7μm), about 6 μm or less (e.g., about 0.1 μm to about 6 μm), about 5 μmor less (e.g., less than 5 μm, about 0.1 μm to about 5 μm), about 4 μmor less (e.g., 0.1 μm to about 4 μm), about 3 μm or less (e.g., 0.1 μmto about 3 μm), about 2 μm or less (e.g., 0.1 μm to about 2 μm), about 1μm or less (e.g., 0.1 μm to about 1 μm), about 0.5 μm to about 6 μm,about 0.5 μm to about 5 μm, about 0.5 μm to about 4 μm, about 0.5 μm toabout 3 μm, or about 0.5 μm to about 2 μm as measured by HELOS/RODOS at1.0 bar. In an exemplary embodiment, the dry particles of the subjecttechnology have a VMGD as measured by HELOS/RODOS at 1.0 bar of about1.3 to about 1.7 μm. In another exemplary embodiment, the dry particlesof the subject technology have a VMGD as measured by HELOS/RODOS at 1.0bar of about 0.5 μm to about 2 μm.

In certain embodiments, the dry particles of the subject technology arelarge and preferably dispersible. For example, the dry particles of thesubject technology may have a VMGD as measured by HELOS/RODOS at 1.0 barof about 30 μm or less (e.g., about 5 μm to about 30 μm). Preferably,the dry particles of the subject technology have an VMGD of about 25 μmor less (e.g., about 5 μm to about 25 μm), about 20 μm or less (e.g.,about 5 μm to about 20 μm), about 15 μm or less (e.g., about 5 μm toabout 15 μm), about 12 μm or less (e.g., about 5 prn to about 12 μm),about 10 μm or less (e.g., about 5 μm to about 10 μm), or about 8 μm orless (e.g., 6 μm to about 8 μm) as measured by HELOS/RODOS at 1.0 bar.

The dry powders described herein can comprise a mixture of largeparticles and small particles.

Preferably, whether the particles are small or large, the dry particlesof the subject technology are dispersible, and have ¼ bar and/or 0.5/4bar of about 2.2 or less (e.g., about 1.0 to about 2.2) or about 2.0 orless (e.g., about 1.0 to about 2.0). Preferably, the dry particles ofthe subject technology have ¼ bar and/or 0.5/4 bar of about 1.9 or less(e.g., about 1.0 to about 1.9), about 1.8 or less (e.g., about 1.0 toabout 1.8), about 1.7 or less (e.g., about 1.0 to about 1.7), about 1.6or less (e.g., about 1.0 to about 1.6), about 1.5 or less (e.g., about1.0 to about 1.5), about 1.4 or less (e.g., about 1.0 to about 1.4),about 1.3 or less (e.g., less than 1.3, about 1.0 to about 1.3), about1.2 or less (e.g., 1.0 to about 1.2), about 1.1 or less (e.g., 1.0 toabout 1.1 μm) or the dry particles of the subject technology have ¼ barof about 1.0.

Alternatively or in addition, the respirable dry particles of thesubject technology can have an MMAD of about 10 μm or less, such as anMMAD of about 0.5 μm to about 10 μm. Preferably, the dry particles ofthe subject technology have an MMAD of about 5 μm or less (e.g. about0.5 μm to about 5 μm, preferably about 1 μm to about 5 μm), about 4 μmor less (e.g., about 1 μm to about 4 μm), about 3.8 μm or less (e.g.about 1 μm to about 3.8 μm), about 3.5 μm or less (e.g. about 1 μm toabout 3.5 μm), about 3.2 μm or less (e.g. about 1 μm to about 3.2 μm),about 3 μm or less (e.g. about 1 μm to about 3.0 μm), about 2.8 μm orless (e.g. about 1 μm to about 2.8 μm), about 2.2 μm or less (e.g. about1 μm to about 2.2 μm), about 2.0 μm or less (e.g. about 1 μm to about2.0 μm) or about 1.8 μm or less (e.g. about 1 micron to about 1.8 μm).

Alternatively or in addition, the dry powders and dry particles of thesubject technology have a FPF of less than 5.0 μm (FPF_TD<5.0 μm) of atleast about 20%, at least about 30%, at least about 45%, preferably atleast about 40%, at least about 45%, at least about 50%, at least about60%, at least about 65% or at least about 70%. Alternatively or inaddition, the dry powders and dry particles of the subject technologyhave a FPF of less than 5.0 μm of the emitted dose (FPF_ED<5.0 μm) of atleast about 45%, preferably at least about 50%, at least about 60%, atleast about 65%, at least about 70%, at least about 75%, at least about80%, or at least about 85%.

Alternatively or in addition, the respirable dry powders and dryparticles of the invention can have an FPF of less than about 5.6 μm(FPF<5.6 μm) of at least about 20%, at least about 30%, at least about40%, preferably at least about 45%, at least about 50%, at least about55%, at least about 60%, at least about 65%, or at least about 70%.

Alternatively or in addition, the dry powders and dry particles of theinvention can have an FPF of less than about 3.4 μm (FPF<3.4 μm) of atleast about 20%, preferably at least about 25%, at least about 30%, atleast about 35%, at least about 40%, at least about 45%, at least about50%, or at least about 55%.

Alternatively or in addition, the respirable dry powders and dryparticles of the subject technology have a tap density of about 0.1g/cm³ to about 1.0 g/cm³. For example, the small and dispersible dryparticles have a tap density of about 0.1 g/cm³ to about 0.9 g/cm³, 0.2g/cm³ to about 0.9 g/cm³, about 0.2 g/cm³ to about 0.9 g/cm³, about 0.3g/cm³ to about 0.9 g/cm³, about 0.4 g/cm³ to about 0.9 g/cm³, about 0.5g/cm³ to about 0.9 g/cm³, or about 0.5 g/cm³ to about 0.8 g/cm³, greaterthan about 0.4 g/cc, greater than about 0.5 g/cc, greater than about 0.6g/cc, greater than about 0.7 g/cc, about 0.1 g/cm³ to about 0.8 g/cm³,about 0.1 g/cm³ to about 0.7 g/cm³, about 0.1 g/cm³ to about 0.6 g/cm³,about 0.1 g/cm³ to about 0.5 g/cm³, about 0.1 g/cm³ to about 0.4 g/cm³,about 0.1 g/cm³ to about 0.3 g/cm³, less than 0.3 g/cm³. In a preferredembodiment, tap density is greater than about 0.4 g/cc. In anotherpreferred embodiment, tap density is greater than about 0.5 g/cc.Alternatively, tap density is less than about 0.4 g/cc.

Alternatively or in addition, the respirable dry powders and dryparticles of the subject technology can have a water or solvent contentof less than about 15% by weight of the respirable dry particle. Forexample, the respirable dry particles of the subject technology can havea water or solvent content of less than about 15% by weight, less thanabout 13% by weight, less than about 11.5% by weight, less than about10% by weight, less than about 9% by weight, less than about 8% byweight, less than about 7% by weight, less than about 6% by weight, lessthan about 5% by weight, less than about 4% by weight, less than about3% by weight, less than about 2% by weight, less than about 1% by weightor be anhydrous. The respirable dry particles of the subject technologycan have a water or solvent content of less than about 6% and greaterthan about 1%, less than about 5.5% and greater than about 1.5%, lessthan about 5% and greater than about 2%, about 2%, about 2.5%, about 3%,about 3.5%, about 4%, about 4.5% about 5%.

Depending on the specific applications of the dry powders describedherein, the dry powder and particles may contain a low or highpercentage of active ingredient in the composition. For example, the dryparticles may contain 3% or more, 5% or more, 10% or more, 15% or more,20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 50% ormore, 60% or more, 70% or more, 75% or more, 80% or more, 85%© or more,90% or more, or 95% or more (weight percentage) of the active ingredient(e.g., acetylsalicylic acid).

5. Delivery of Dry Powders

Through some of the embodiments disclosed herein, Applicants haveovercome the challenges acknowledged by prior teachings. In particular,Applicants have recognized that when a drug is inhaled into the lungs,the drug can be dispersed toward the alveoli. Although alveoli primarilyfunction to exchange carbon dioxide for oxygen, alveoli also produceenzymes. Thus, inhaled substances, such as pathogens, drugs, or otherchemicals, may be processed at the alveoli.

An alveolus comprises a network of elastic fibers and capillaries,resembling a woven sphere on its outer surface. The capillaries functionto carry oxygen depleted blood toward the lungs and oxygen rich bloodaway from the lungs, via the pulmonary artery and the pulmonary vein.The interior of each alveoli comprises a thin tissue known as analveolar lining or epithelium. Alveolar epithelium is made of twodistinct types of cells, known as flat type I and type II. Flat type Icells cover most of the surface area of the epithelium and are closelyspaced, allowing only small molecules to pass therebetween, such asoxygen and carbon dioxide. Type II alveolar cells aid in producing thepulmonary surfactant used in gas exchange. Further, the alveolarepithelium also comprises macrophages, which assist in disposing of fineparticulate foreign matter such as dust, tar, and pathogens. Despite thediminutive size of the alveoli (being only approximately 250 μm),because an adult can have between 200 million and 400 million alveoli,the alveolar respiratory surface area can be from approximately 1,400 toabout 1,600 square feet.

According to some embodiments disclosed herein, absorption of NSAIDsadministered by DPI or MDI through the pulmonary capillaries andepithelium can provide an immediately effective treatment to addresssymptoms of thromboembolic events. One of the novel realizations of someembodiments is that the substantial first pass effect produced by oraladministration of NSAIDs, such as aspirin, can be avoided throughadministration by dry powder inhaler. In addition, there has hithertobeen no teaching or suggestion regarding the pharmacokinetics of drypowder delivery of a NSAID, such as aspirin, and the possible metabolismor inactivation of the drug as it encounters the endothelial tissue ofthe pulmonary capillaries.

The delivery of a NSAID by DPI or MDI is a complex and unpredictabletechnological area that has not provided straightforward or expectedresults to a person of skill in the art. Accordingly, there has been noreason for a person of skill to believe that a combination of priorsystems or treatment methods could produce the embodiments disclosedherein. For example, some embodiments herein recognize an unexpectedresult that as a drug crosses the endothelium of pulmonary arteries andalveoli, the first pass effect is minimized and results in a much lowerrate of the activation of the drug than in other drug delivery pathways.

The endothelium of the pulmonary capillaries serves as a barrier byselectively allowing materials to exit or enter the bloodstream. Itwould be expected that aspirin would be inactivated in the pulmonarycapillaries, which are lined by endothelial cells. The endothelial cellsare extremely metabolically active. Thus, a person of skill would expectthat aspirin would be inactivated by the endothelium of the pulmonarycapillaries. However, according to some embodiments disclosed herein, itis contemplated that as the powdered drug encounters the endothelium,the endothelium can metabolize or activate a much smaller portion of thepowdered drug compared to the metabolism provided by the gut and liver.For example, after being transformed in the stomach to salicylic acid,as much as 80% of the salicylic acid is metabolized in the liver. Thus,only a small minority of the salicylic acid is bioavailable to thesystemic blood stream.

However, it is contemplated that a vast majority of the salicylic acidmetabolized from the inhaled aspirin powder will be bioavailable to thesystemic blood stream. Thus, a dose of much less than that of a babyaspirin (e.g., less than 81 mg) can be provided by dry powderinhalation. This can provide a much lower dosage while providing abioequivalent dosage.

Further, in accordance an aspect of some embodiments, it is contemplatedthat an analogous first pass effect may be experienced in theendothelium of the pulmonary capillaries. Accordingly, with regard tothe provision of an inhaled dosage that is the bioequivalent of a babyaspirin administered orally, the inhaled dosage should account for somefirst pass effect experience through the endothelium of the pulmonarycapillaries.

In accordance with some embodiments, the first pass effect through theendothelium of the pulmonary capillaries can be a minimum, whichprovides little overall effect on the inhaled dosage.

However, it is also contemplated that in some embodiments, the firstpass effect through the endothelium of the pulmonary capillaries can beentirely negligible. Thus, the amount of the inhaled dosage need not beadjusted to compensate for first pass effect through the pulmonarycapillaries.

Therefore, some embodiments recognize the unexpected result that evenextremely low doses of aspirin (and likely other NSAIDs) can provide asignificant therapeutic effect while providing de minimus orinconsequential side effects. For example, doses as low as 1 mg, 2 mg, 3mg, 4 mg, or 5 mg of acetylsalicylic acid can be effective in reducingthe risk of a thromboembolic event. Accordingly, the net benefitsincreased dramatically at significantly lower doses, according to someembodiments. These results and outcomes are unexpected given the complexand unpredictable nature of drug interactions in the body, drug deliverypathways, and microscopic drug structures. Finally, no teachings orother prior references disclose a system or process for achievingtherapeutically beneficial results while substantially avoiding anynegative side effects using DPI or MDI drug delivery mechanisms withmicroscopic NSAIDs.

In accordance with some embodiments, the dry powder administration ofthe NSAID, such as a salicylate like acetylsalicylic acid, can compriseparticles having a median aerodynamic diameter of from about 1 μm toabout 5 μm, as discussed above. The particles can be highly porous anddemonstrate a sponge-like morphology or be a component of a carrierparticle. The particles can also demonstrate a spheroidal shape, bywhich the shape and porous surface can serve to decrease the area ofcontact between particles, thereby leading to less particleagglomeration and more effective distribution throughout the lung. Drypowder technologies, such as PulmoSphere™, may be implemented inembodiments of the methods and systems disclosed herein.

Referring to FIG. 1, in a dry powder inhalation technique, a patient canuse a dry powder inhaler 10 to inhale a powder formulation of a drug,such as a NSAID. The dose is effective to reduce a risk of athromboembolic event in the patient. An aspect of some embodiments isthe realization that because the lung is an efficient filter, itgenerally only permits particles having a size of less than 5 μm. Forexample, after the drug enters the main stem bronchus 20, the drug willenter each lung 22, 24. The drug can then pass through the bronchialtrees 26, 28 until reaching the individual alveoli 30 in the lungs 22,24, which are exceedingly numerous, as discussed below. Of each longThus, the dry powder inhaler 10 can allow the patient to self administera dosage of particles having a size of from about 1 μm and about 5 μm.In some embodiments, the particle size can be from about 2 μm to about 4μm.

According to some embodiments, various types of inhalers can be used toprovide the drug using a DPI or MDI delivery system. The doseadministered can be effective to reduce a risk of a thromboembolic eventin a patient.

For example, the dry powder inhaler 10 can comprise a mouthpiece, areservoir for receiving the NSAID, and an actuation member for makingavailable the NSAID for inhalation by a patient through the mouthpiece.

For example, FIGS. 2A-2F illustrate a DPI delivery device 100 having amouthpiece 102 and a drug compartment 104. The drug compartment 104 canbe inserted into an inhaler body cavity 110.

For example, as shown in FIG. 2B, the drug compartment 104 can beinserted into the body cavity 110 into a stowed position 120 for storagepurposes. However, the drug compartment 104 can also be moved to a firstposition 122, shown in FIG. 2C, in which a first receptacle 140 of thedrug compartment 104 is aligned with a mouthpiece airway 142. In thisfirst position 122, the drug contained in the first receptacle 140 canbe delivered through the mouthpiece airway 142 to be inhaled by thepatient, as illustrated in FIG. 2D.

Additionally, as shown in FIG. 2E, the drug compartment 104 can be movedto a second position 124 in which a second receptacle 144 is alignedwith the mouthpiece airway 142. Thus position, the drug contained in thesecond receptacle 144 can be inhaled by the patient, as illustrated inFIG. 2F.

In the process of breathing, the lungs are normally continuously exposedto materials present in the environment of a variety of sizes. This caninclude pollens (20-90 μm), bacteria (0.2-200 μm), and smokeparticulates (0.01-1 μm). Deposition of a particular particle depends ona number of factors, including the size and density of the particle, aswell as the velocity of flow of air into and out of the lungs, and theresident time of the particle in the respiratory system. Moreover, thehuman body has developed systems to protect against adverse effects ofsome of these inhaled substances, including such processes asphagocytosis. Thus, one factor to consider when designing systems andmethods for delivering a pharmaceutical compound via inhalation is theeffect that particle size has on the location in the respiratory tractwhere drug particles are likely to become deposited after inhalation.

Particles that enter the lungs are deposited along the course of therespiratory tract by impaction, sedimentation and diffusion. Often, thebehavior of particles within an airflow stream can be described byaerodynamic diameter, as described in detail herein. Like the Reynold'snumber concept in aerodynamics, two particles having the sameaerodynamic diameter will behave fundamentally the same in an airflow,regardless of their actual geometric (i.e., physical) size.

Previously it has been shown that particle size, or more accurately,aerodynamic diameter, significantly affects the location within therespiratory system where particles are most likely to become depositedafter inspiration. For example, Heyder et al. (J. Aerosol. Sci. 17,811-825, 1986) examined deposition of particles ranging in size from 5nm to 15 μm in the respiratory tract. Their studies indicated thatparticles with an aerodynamic diameter greater than 5 μm depositpredominantly by inertial impaction in the mouth and upper airways.Smaller particles, (aerodynamic diameter ranging from 1-5 μm) depositdeeper in the lungs by impaction and sedimentation, while very smallparticles (aerodynamic diameter<1 μm), mainly remain suspended in theairflow and are exhaled.

Others have obtained similar results, suggesting that for delivery ofdrugs to the lungs, particles with an median aerodynamic diameter ofabout 2 μm are likely to be efficiently deposited in the alveolarspaces, with fractional deposition approaching 90% of the deliveredparticle dose (Byron, 1986, J. Pharm. Sci. 75(5), 433-438). In contrast,where particles have an median aerodynamic diameter ranging from 5-10μm, only about 10% of the delivered dose will deposit in the alveoli,with about 40% depositing in the airways, and the remainder in the oralcavity and pharynx. Where median aerodynamic diameter is 15 μm orgreater, particles deposit predominantly in the oral cavity and pharynx.Given the proximity of the alveolar epithelium to the systemiccirculation, and the known benefit of delivering drugs to the lungs inorder to avoid loss of a pharmaceutical agent through hydrolysis in thegut, or first pass effects due to processing in the liver, there is thusan advantage gained by designing a powdered drug composition that willbe most effectively delivered to and deposited in the respiratory tract,and in particular the alveolar spaces.

Further advantages are gained by deposition of drugs in the alveolarspaces. For example, their large effective surface area spaces, and thereduced thickness of the alveolar epithelium, provides nearly immediatetransfer of a drug to the circulatory system. Similarly, as the bloodleaving the alveolar capillaries first travels back to the heart via thepulmonary vein, significant levels of a therapeutic molecule can beachieved in the vicinity of the heart nearly immediately. This is aparticular advantage in designing treatments for cardiovascularconditions as in the present case.

Thus, an anti-thromboembolic agent such as an NSAID can be delivered ata higher plasma concentration than would otherwise be possible with anequivalent amount of an orally administered dose of the agent, and theselevels can be achieved more rapidly by delivery to the lungs as comparedto oral administration. Thus, those of skill in the art will appreciatethat it will be possible to achieve circulating plasma levels of anNSAID in the coronary circulation effective to reduce the risk of athromboembolic event, with a lower a administered dosage than would berequired if the NSAID were taken orally as per the currentrecommendation of physicians.

As described herein, one aspect of the subject technology provides anapparatus and method for providing a therapeutically effective dose ofan NSAID in order to reduce the risk of a thromboembolic event. Asdiscussed above, the general approach is to deliver an NSAID in apharmaceutically acceptable powdered form (e.g., Acetylsalicylic acid,and/or derivatives thereof “ASA”) by means of an inhaler. However, thereare a number of challenges in delivering therapeutically effectiveamounts of an NSAID by a dry powder inhalations system.

One challenge in designing such treatment system is the limit in termsof the size of the dose that can be comfortably tolerated by thepatient. For example, in some cases, it has been shown that about 40 toabout 50 mg of powdered compound can be comfortably delivered in asingle inhaled dose. Coincidentally, no currently available inhalerapparatus is capable of delivering more than about 50 mg of a powder perdelivery. However, the recommended dosage for ASA in order to treatsuspected symptoms consistent with impending myocardial infarct are tochew two 81 mg tablets of ASA. Thus, the recommended dose for suchtreatment is about 160 mg. This suggests that in order to provide theidentical amount of ASA as recommended by oral administration, a patientmay have to take as many as four inhaled doses within the same timeperiod. Studies have shown that patients can realistically take fiveinhaled doses within one minute, using currently available inhalertechnology.

As discussed above, there is a general trend that deposition of particlein the alveolar spaces increases as particle size is reduced. Studies onnanoparticle distribution have shown that inhaled nanoparticles having asize <100 nm are desirable for alveolar deposition as well as forminimizing lung phagocytosis (Hoet et al., 2004, J. Nanbiotechnol. 2,doi:10.1186/1477-3155-2-12). Nanoparticles provide additional advantagesin terms of dispersion of the active compound and ultimately in the rateof uptake as compared to coarser preparations, the most obvious of whichis that smaller particles tend to disperse and solubilize faster thanlarger ones. However, particles of nanometer size are not optimal foruse in the delivery of a powdered pharmaceutical, as they tend not todeposit efficiently, but remain suspended in the airflow and areexpelled upon exhalation.

One way in which to overcome this problem is through the use of methodsto produce particles comprising aggregates of nanoparticles havingoptimal average aerodynamic size for efficient alveolar deposition. Forexample, Hadinoto et al. (2004, Int. J. Pharma., doi:10.1016/j.ijpharm.2007.03.035) have shown that large hollow shellscomprising nanoparticles can be produced by a spray-drying method. Whilethese particles have a large geometric diameter (10-15 μm), they have asmall aerodynamic diameter (1-3 μm) that is desirable for delivery ofcompounds to deeper regions of the lungs. Moreover, these large hollowshells rapidly disaggregate into the constituent nanoparticles providingrapid release of the pharmaceutical agent. In addition, Hadinoto et al.have shown that this method is adaptable to producing preparations ofASA for used in powder inhaler devices. Thus, using these methods incombination with subject technology it is possible to achieve ASAparticles of an aerodynamic size for deposition to alveolar spaces, andwhere over 90% of the drug is released from the particles within 30minutes.

However, despite the ability to make particles of an optimal size, thereis an additional problem in preparing pharmaceutical compositions foruse via inhalation. Typically, it has been observed that powders ofuniform size, tend to clump and form larger aggregates via a phenomenonknown as bridging. Particle when bridged behave aerodynamically as muchlarger particles, and as discussed above, will tend not to reach thealveolar spaces, which are desired for optimum rapid delivery of thedrug of interest. In order to reduce aggregation of the pharmaceuticallyactive agent, drugs are often blended with excipient particles such aslactose for example in order to inhibit aggregation. While the additionof excipients is an effective method to inhibit aggregation, theiraddition reduces the amount of the pharmaceutically active compound permeasured inhaled dose. The result would be that a patient would have totake a greater number of doses in order to achieve the same intake ofthe pharmaceutically active compound. In an emergency situation, thismay be impractical. For example, if a preparation were made that was 50%ASA ingredient and 50% excipient, with a limit of 40 mg of powder perdose, a person would have to inhale about 8 doses in order to take therecommended 162 mg of ASA for treatment of symptom suggestive of animpending infarct. Such a situation may make dry powder inhalers lesspractical.

However, in the present case, the inventors have now discovered thatmixing particles of the same active ingredient (e.g., ASA), usingbatches of particles having different size distributions, can reducebridging. For example, while a composition having a relatively uniformparticle size will aggregate, providing a blended composition havingsome particles with a median aerodynamic diameter in a range from about1 μm to about 5 μm, other particles with a median aerodynamic diameterin a range from about 5 μm to about 15 μm, and still other particleswith a median aerodynamic diameter greater than about 15 μm, willinhibit aggregation and maintain the deposition characteristics of thepreparation. In effect, the pharmaceutically active compound is used toreplace the function of an excipient (such as lactose) with respect topreventing aggregation during storage of the medicament. To theknowledge of the inventor, no one has considered using thepharmaceutically active ingredient as its own excipient for the purposesof inhibiting aggregation.

In addition, and unlike many other drugs, NSAIDs, and in particular ASA,are able to enter the circulatory system effectively through routesother than through the epithelium of the alveoli. Notably, ASA is ableto enter the body by absorption through the mucosal layers of the oralcavity, as well as the pharynx and undoubtedly the epithelium of theairways. Thus, regardless of particle size, it will be appreciated thatby providing an inhalable form of ASA, the inhaled dosage can besubstantially taken up into the systemic circulation, and be effectiveto reduce the risk of a thromboembolic event.

In addition, by selecting the proportions of the various particle sizes,one can provide formulations that are faster or slower acting, based onthe location of where the drug is ultimately deposited. For example, insome embodiments it may be desirable to provide a preparation thatcomprises 80% ASA particles with a median aerodynamic diameter of about1 μm to about 5 μm, and about 20% of particles with a median aerodynamicdiameter of at least 15 μm. Other combinations are possible as well, andthose of skill in the art will readily appreciate that faster actingpreparations will comprise proportionately more smaller particles, whileslower acting preparations will comprise proportionately more largeparticles. Thus, using the apparatus and methods described herein it istherefore possible to provide a therapeutically effective dose of anNSAID such as ASA via the respiratory tract, at least as rapidly as canbe achieved by oral dosing.

Where a slower acting dosages form was desired, the formulation couldinclude increasing fractions of particles with a median aerodynamicdiameter in the range from about 5 μm to about 10 μm, or 15 μm orgreater. These preparations would result in deposition in either theairways or oral cavity and pharynx and thus provide a more gradualincrease in circulating levels of ASA and its metabolic derivatives.

In either case, the subject technology provides formulations that candeliver ASA and its pharmacologically active metabolic byproducts (e.g.,salicylate) to the systemic circulation at least as quickly if not morequickly than can be accomplished via oral administration. In addition,the present formulations are effective to deliver ASA and itspharmacologically active metabolic byproducts to the systemiccirculation at levels at least equal to that observed after oraladministration of an equivalent dose of ASA.

For example, pharmacokinetic studies show that after oral administrationof ASA peak plasma levels are achieved after about 20 minutes, afterwhich they rapidly decline due to the relatively short eliminationhalf-life (15-20 minutes). By comparison, plasma levels of the primarypharmacologically active metabolite salicylate, increase for a period ofabout 45 minutes following administration of ASA, and remain elevatedfor much longer due to its significantly longer elimination half-life(2-3 hr) (Dressman et al., 2012, Biowaiver Monograph forImmediate-Release Solid Oral Dosage Forms: Acetylsalicylic Acid, doi10.1002/jps.2312).

Significantly, the pharmacokinetic behavior of ASA has been found to belinear over a dosage range from 30-400 mg. Extrapolating from thesedata, one would therefore expect that peak circulating plasma levels ofASA and SA would be approximately 4 mcg/mL and 10 mcg/mL respectivelyand with the same temporal kinetics as discussed above.

Accordingly, one aspect of the subject technology provides a dry powderthat comprises a mixture of particles of various sizes.

For example, the dry powder can comprise particles of large sizes, asmeasured by VMGD (e.g., VMGD≥15 μm, such as ≥20 μm or 20-30 μm) and ofsmall sizes, measured by VMGD (e.g., VMGD≤5 μm, such as 1-3 μm) at aratio (w:w) of: about 1:1, about 1:2, about 1:3, about 1:4, about 1:5,about 1:6, about 1:7, about 1:8, about 1:10, about 1:15, about 1:20,about 1:25, about 1:30, about 1:40, about 1:50, about 1:100, about 2:1,about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about9:1, about 10:1, about 15:1, about 20:1, about 25:1, about 30:1, about40:1, about 50:1, or about 100:1, etc.

Alternatively or in addition, the dry powder can comprise: about 1%,about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about35%, about 40%, about 45%, about 50%, about 55%, about 50%, about 55%,about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about90%, about 95%, or about 99% (weight percentage) of particles havingVMGD of about 10 μm or less, preferably about 5 μm or less. Particles of10 μm or less generally can reach lungs, and particles of 5 μm or less(e.g., 1-3 μm) generally can reach alveoli.

Alternatively or in addition, the dry powder can comprise: about 1%,about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about35%, about 40%, about 45%, about 50%, about 55%, about 50%, about 55%,about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about90%, about 95%, or about 99% (weight percentage) of particles havingVMGD of between about 5 μm to about 20 μm, preferably between about 5 μmto about 15 μm, or between about 5 μm to about 10 μm.

Alternatively or in addition, the dry powder can comprise: about 1%,about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about35%, about 40%, about 45%, about 50%, about 55%, about 50%, about 55%,about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about90%, about 95%, or about 99% (weight percentage) of particles havingVMGD of about 15 μm or more, preferably 20 μm or more.

The above features can be combined. For example, the dry power cancomprise about 50% of particles of about 5 μm or less (VMGD), about 25%of particles of about 5 to about 15 μm (VMGD), and about 25% ofparticles of about 15 μm or more (VMGD).

The dry powder can also comprise a mixture of particles having variousmass median aerodynamic diameters (MMAD). For example, the dry powdercan comprise particles of large sizes (e.g., MMAD≥15 μm, such as ≥20 μmor 20-30 μm) and of small sizes (e.g., MMAD≤5 μm, such as 1-3 μm) at aratio (w:w) of: about 1:1, about 1:2, about 1:3, about 1:4, about 1:5,about 1:6, about 1:7, about 1:8, about 1:10, about 1:15, about 1:20,about 1:25, about 1:30, about 1:40, about 1:50, about 1:100, about 2:1,about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1, about9:1, about 10:1, about 15:1, about 20:1, about 25:1, about 30:1, about40:1, about 50:1, or about 100:1, etc

Alternatively or in addition, the dry powder can comprise: about 1%,about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about35%, about 40%, about 45%, about 50%, about 55%, about 50%, about 55%,about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about90%, about 95%, or about 99% (weight percentage) of particles havingMMAD of about 10 μm or less, preferably about 5 μm or less. Particles of10 μm or less generally can reach lungs, and particles of 5 μm or less(e.g., 1-3 μm) generally can reach alveoli.

Alternatively or in addition, the dry powder can comprise: about 1%,about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about35%, about 40%, about 45%, about 50%, about 55%, about 50%, about 55%,about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about90%, about 95%, or about 99% (weight percentage) of particles havingMMAD of between about 5 μm to about 20 μm, preferably between about 5 μmto about 15 μm, or between about 5 μm to about 10 μm.

Alternatively or in addition, the dry powder can comprise: about 1%,about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about35%, about 40%, about 45%, about 50%, about 55%, about 50%, about 55%,about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about90%, about 95%, or about 99% (weight percentage) of particles havingMMAD of about 15 μm or more, preferably 20 μm or more.

The above features can be combined. For example, the dry power cancomprise about 50% of particles of about 5 μm or less (MMAD), about 25%of particles of about 5 to about 15 μm (MMAD), and about 25% ofparticles of about 15 μm or more (MMAD).

In some embodiments, the dry powder does not comprise, or does notsubstantially comprise, an excipient. In some embodiments, the drypowder does not comprise, or does not substantially comprise, ananti-aggregation (or anti-bridging) excipient.

In certain embodiments, the dry powder comprises a mixture of particlesof various sizes, and is effective to substantially prevent or reduceparticle bridging. In certain embodiment, at least about 40%, at leastabout 45%, at least about 50%, at least about 55%, at least about 60%,at least about 65%, at least about 70%, at least about 75%, at least80%, at least about 85%, or at least about 90% of the NSAID (such asacetylsalicylic acid) in the dry powder is delivered to the alveolarspaces of a lung.

6. Methods for Preparing Dry Powders and Dry Particles

The respirable dry particles and dry powders can be prepared using anysuitable method. Many suitable methods for preparing respirable drypowders and particles are conventional in the art, and include singleand double emulsion solvent evaporation, spray drying, milling (e.g.,jet milling), blending, solvent extraction, solvent evaporation, phaseseparation, simple and complex coacervation, interfacial polymerization,suitable methods that involve the use of supercritical carbon dioxide(CO₂), and other suitable methods. Respirable dry particles can be madeusing methods for making microspheres or microcapsules known in the art.These methods can be employed under conditions that result in theformation of respirable dry particles with desired aerodynamicproperties (e.g., aerodynamic diameter and geometric diameter). Ifdesired, respirable dry particles with desired properties, such as sizeand density, can be selected using suitable methods, such as sieving.

The respirable dry particles can be spray dried. Suitable spray-dryingtechniques are described, for example, by K. Masters in “Spray DryingHandbook”, John Wiley & Sons, New York (1984); and spray dryingtechniques developed by BUCHI Laboratory Equipment or GEA Niro dryingtechnology. Generally, during spray-drying, heat from a hot gas such asheated air or nitrogen is used to evaporate a solvent from dropletsformed by atomizing a continuous liquid feed. If desired, the spraydrying or other instruments, e.g., jet milling instrument, used toprepare the dry particles can include an inline geometric particle sizerthat determines a geometric diameter of the respirable dry particles asthey are being produced, and/or an inline aerodynamic particle sizerthat determines the aerodynamic diameter of the respirable dry particlesas they are being produced.

For spray drying, solutions, emulsions or suspensions that contain thecomponents of the dry particles to be produced in a suitable solvent(e.g., aqueous solvent, organic solvent, aqueous-organic mixture oremulsion) are distributed to a drying vessel via an atomization device.For example, a nozzle or a rotary atomizer may be used to distribute thesolution or suspension to the drying vessel. For example, a rotaryatomizer having a 4- or 24-vaned wheel may be used. Examples of suitablespray dryers that can be outfitted with either a rotary atomizer or anozzle, include, Mobile Minor Spray Dryer or the Model PSD-1, bothmanufactured by Niro, Inc. (Denmark). Actual spray drying conditionswill vary depending, in part, on the composition of the spray dryingsolution or suspension and material flow rates. The person of ordinaryskill will be able to determine appropriate conditions based on thecompositions of the solution, emulsion or suspension to be spray dried,the desired particle properties and other factors. In general, the inlettemperature to the spray dryer is about 100° C. to about 300° C., andpreferably is about 220° C. to about 285° C. The spray dryer outlettemperature will vary depending upon such factors as the feedtemperature and the properties of the materials being dried. Generally,the outlet temperature is about 50° C. to about 150° C., preferablyabout 90° C. to about 120° C., or about 98° C. to about 108° C. Ifdesired, the respirable dry particles that are produced can befractionated by volumetric size, for example, using a sieve, orfractioned by aerodynamic size, for example, using a cyclone, and/orfurther separated according to density using techniques known to thoseof skill in the art.

To prepare the respirable dry particles of the subject technology,generally, a solution, emulsions or suspension that contains the desiredcomponents of the dry powder (i.e., a feed stock) is prepared and spraydried under suitable conditions. Preferably, the dissolved or suspendedsolids concentration in the feed stock is at least about 1 g/L, at leastabout 2 g/L, at least about 5 g/L, at least about 10 g/L, at least about15 g/L, at least about 20 g/L, at least about 30 g/L, at least about 40g/L, at least about 50 g/L, at least about 60 g/L, at least about 70g/L, at least about 80 g/L, at least about 90 g/L, or at least about 100g/L. The feed stock can be provided by preparing a single solution orsuspension by dissolving or suspending suitable components (e.g., salts,excipients, other active ingredients) in a suitable solvent. Thesolvent, emulsion or suspension can be prepared using any suitablemethods, such as bulk mixing of dry and/or liquid components or staticmixing of liquid components to form a combination. For example, ahydrophillic component (e.g., an aqueous solution) and a hydrophobiccomponent (e.g., an organic solution) can be combined using a staticmixer to form a combination. The combination can then be atomized toproduce droplets, which are dried to form respirable dry particles.Preferably, the atomizing step is performed immediately after thecomponents are combined in the static mixer.

In one example, respirable dry particles that comprise acetylsalicylicacid and sodium citrate are prepared by spray drying.

The feed stock, or components of the feed stock, can be prepared usingany suitable solvent, such as an organic solvent, an aqueous solvent ormixtures thereof. Suitable organic solvents that can be employed includebut are not limited to alcohols such as, for example, ethanol, methanol,propanol, isopropanol, butanols, and others. Other organic solventsinclude but are not limited to perfluorocarbons, dichloromethane,chloroform, ether, ethyl acetate, methyl tert-butyl ether and others.Co-solvents that can be employed include an aqueous solvent and anorganic solvent, such as, but not limited to, the organic solvents asdescribed above. Aqueous solvents include water and buffered solutions(such as phosphate buffer).

The feed stock or components of the feed stock can have any desired pH,viscosity or other properties. If desired, a pH buffer can be added tothe solvent or co-solvent or to the formed mixture. Generally, the pH ofthe mixture ranges from about 3 to about 8.

Respirable particles can also be produced by jet-milling. See, e.g.,techniques developed by Apex Process Technology or Jetpharma SA. Jetmilling is a process of using highly compressed air or other gasses,usually in a vortex motion, to impact fine particles against each otherin a chamber. Jet mills are capable of reducing solids to particle sizesin the low-micron to submicron range. The grinding energy is created bygas streams from horizontal grinding air nozzles. Particles in thefluidized bed created by the gas streams are accelerated towards thecentre of the mill, colliding with slower moving particles. The gasstreams and the particles carried in them create a violent turbulenceand as the particles collide with one another they are pulverized.

Wet polishing is a process that combines a technology to attain a smallparticle size (either a bottom up technique such as controlledcrystallization or nanocrystallization or top down technique such ashigh shear mixing or high pressure homogenization) with a suitableisolation technology (for example spray drying or filtration with adrying process). See, e.g., techniques developed by Hovione. Thesecombinations can be used to tune the particle size and morphology tomeet specific drug delivery needs. The method allows control of particlesize distribution with tight spans and in-process sampling, andmaintains crystalline state (little or no amorphous content).

Wet polishing technique can be repeated multiple times to achieve aparticular size of about 500 nanometers or less.

Particles described herein can be encapsulated, e.g., by apharmaceutical excipient such as lactose, sugar, or a polymer.

The above techniques can be combined. For example, after going throughthe wet polishing process, the particles can go through a spray dryingprocess (e.g., for the purpose of micro-encapsulation).

Respirable dry particles and dry powders can be fabricated and thenseparated, for example, by filtration or centrifugation by means of acyclone, to provide a particle sample with a preselected sizedistribution. For example, greater than about 30%, greater than about40%, greater than about 50%, greater than about 60%, greater than about70%, greater than about 80%, or greater than about 90% of the respirabledry particles in a sample can have a diameter within a selected range.The selected range within which a certain percentage of the respirabledry particles fall can be, for example, any of the size ranges describedherein, such as between about 0.1 to about 3 μm VMGD.

The diameter of the respirable dry particles, for example, their VMGD,can be measured using an electrical zone sensing instrument such as aMultisizer Ile, (Coulter Electronic, Luton, Beds, England), or a laserdiffraction instrument such as a HELOS system (Sympatec, Princeton,N.J.). Other instruments for measuring particle geometric diameter arewell known in the art. The diameter of respirable dry particles in asample will range depending upon factors such as particle compositionand methods of synthesis. The distribution of size of respirable dryparticles in a sample can be selected to permit optimal depositionwithin targeted sites within the respiratory system.

Experimentally, aerodynamic diameter can be determined using time offlight (TOF) measurements. For example, an instrument such as the Model3225 Aerosizer DSP Particle Size Analyzer (Amherst Process Instrument,Inc., Amherst, Mass.) can be used to measure aerodynamic diameter. TheAerosizer measures the time taken for individual respirable dryparticles to pass between two fixed laser beams.

Aerodynamic diameter also can be experimentally determined directlyusing conventional gravitational settling methods, in which the timerequired for a sample of respirable dry particles to settle a certaindistance is measured. Indirect methods for measuring the mass medianaerodynamic diameter include the Andersen Cascade Impactor and themulti-stage liquid impinger (MSLI) methods. The methods and instrumentsfor measuring particle aerodynamic diameter are well known in the art.

Tap density is a measure of the envelope mass density characterizing aparticle. The envelope mass density of a particle of a statisticallyisotropic shape is defined as the mass of the particle divided by theminimum sphere envelope volume within which it can be enclosed. Featureswhich can contribute to low tap density include irregular surfacetexture and porous structure. Tap density can be measured by usinginstruments known to those skilled in the art such as the Dual PlatformMicroprocessor Controlled Tap Density Tester (Vankel, N.C.), a GeoPyc™instrument (Micrometrics Instrument Corp., Norcross, Ga.), or SOTAX TapDensity Tester model TD2 (SOTAX Corp., Horsham, Pa.). Tap density can bedetermined using the method of USP Bulk Density and Tapped Density,United States Pharmacopia convention, Rockville, Md., 10^(th)Supplement, 4950-4951, 1999.

Fine particle fraction can be used as one way to characterize theaerosol performance of a dispersed powder. Fine particle fractiondescribes the size distribution of airborne respirable dry particles.Gravimetric analysis, using a Cascade impactor, is one method ofmeasuring the size distribution, or fine particle fraction, of airbornerespirable dry particles. The Andersen Cascade Impactor (ACI) is aneight-stage impactor that can separate aerosols into nine distinctfractions based on aerodynamic size. The size cutoffs of each stage aredependent upon the flow rate at which the ACI is operated. The ACI ismade up of multiple stages consisting of a series of nozzles (i.e., ajet plate) and an impaction surface (i.e., an impaction disc). At eachstage an aerosol stream passes through the nozzles and impinges upon thesurface. Respirable dry particles in the aerosol stream with a largeenough inertia will impact upon the plate. Smaller respirable dryparticles that do not have enough inertia to impact on the plate willremain in the aerosol stream and be carried to the next stage. Eachsuccessive stage of the ACI has a higher aerosol velocity in the nozzlesso that smaller respirable dry particles can be collected at eachsuccessive stage.

If desired, a two-stage collapsed ACI can also be used to measure fineparticle fraction. The two-stage collapsed ACI consists of only the toptwo stages of the eight-stage ACI and allows for the collection of twoseparate powder fractions. Specifically, a two-stage collapsed ACI iscalibrated so that the fraction of powder that is collected on stage oneis composed of respirable dry particles that have an aerodynamicdiameter of less than 5.6 μm and greater than 3.4 μm. The fraction ofpowder passing stage one and depositing on a collection filter is thuscomposed of respirable dry particles having an aerodynamic diameter ofless than 3.4 μm. The airflow at such a calibration is approximately 60L/min.

The FPF(<5.6) has been demonstrated to correlate to the fraction of thepowder that is able to make it into the lung of the patient, while theFPF(<3.4) has been demonstrated to correlate to the fraction of thepowder that reaches the deep lung of a patient. These correlationsprovide a quantitative indicator that can be used for particleoptimization.

An ACI can be used to approximate the emitted dose, which herein iscalled gravimetric recovered dose and analytical recovered dose.“Gravimetric recovered dose” is defined as the ratio of the powderweighed on all stage filters of the ACI to the nominal dose. “Analyticalrecovered dose” is defined as the ratio of the powder recovered fromrinsing all stages, all stage filters, and the induction port of the ACIto the nominal dose. The FPF_TD(<5.0) is the ratio of the interpolatedamount of powder depositing below 5.0 μm on the ACI to the nominal dose.The FPF_RD(<5.0) is the ratio of the interpolated amount of powderdepositing below 5.0 μm on the ACI to either the gravimetric recovereddose or the analytical recovered dose.

Another way to approximate emitted dose is to determine how much powderleaves its container, e.g. capture or blister, upon actuation of a drypowder inhaler (DPI). This takes into account the percentage leaving thecapsule, but does not take into account any powder depositing on theDPI. The emitted dose is the ratio of the weight of the capsule with thedose before inhaler actuation to the weight of the capsule after inhaleractuation. This measurement can also be called the capsule emmitedpowder mass (CEPM)

A Multi-Stage Liquid Impinger (MSLI) is another device that can be usedto measure fine particle fraction. The Multi-stage liquid Impingeroperates on the same principles as the ACI, although instead of eightstages, MSLI has five. Additionally, each MSLI stage consists of anethanol-wetted glass frit instead of a solid plate. The wetted stage isused to prevent particle bounce and re-entrainment, which can occur whenusing the ACI.

The subject technology also relates to a respirable dry powder orrespirable dry particles produced using any of the methods describedherein.

The respirable dry particles of the subject technology can also becharacterized by the chemical stability of the salts or the excipientsthat the respirable dry particles comprise. The chemical stability ofthe constituent salts can effect important characteristics of therespirable particles including shelf-life, proper storage conditions,acceptable environments for administration, biological compatibility,and effectiveness of the salts. Chemical stability can be assessed usingtechniques well known in the art. One example of a technique that can beused to assess chemical stability is reverse phase high performanceliquid chromatography (RP-HPLC). Respirable dry particles of the subjecttechnology include salts that are generally stable over a long periodtime.

If desired, the respirable dry particles and dry powders describedherein can be further processed to increase stability. An importantcharacteristic of pharmaceutical dry powders is whether they are stableat different temperature and humidity conditions. Unstable powders willabsorb moisture from the environment and agglomerate, thus alteringparticle size distribution of the powder.

Excipients, such as maltodextrin, may be used to create more stableparticles and powders. The maltodextrin may act as an amporphous phasestabilizer and inhibit the components from converting from an amorphousto crystalline state. Alternatively, a post-processing step to help theparticles through the crystallization process in a controlled way (e.g.,on the baghouse at elevated humidity) can be employed with the resultantpowder potentially being further processed to restore theirdispersibility if agglomerates formed during the crystallizationprocess, such as by passing the particles through a cyclone to breakapart the agglomerates. Another possible approach is to optimize aroundprocess conditions that lead to manufacturing particles that are morecrystalline and therefore more stable. Another approach is to usedifferent excipients, or different levels of current excipients toattempt to manufacture more stable forms of the salts.

The respirable dry particles and dry powders described herein aresuitable for inhalation therapies. The respirable dry particles may befabricated with the appropriate material, surface roughness, diameterand tap density for localized delivery to selected regions of therespiratory system such as the deep lung or upper or central airways.For example, higher density or larger respirable dry particles may beused for upper airway delivery, or a mixture of varying size respirabledry particles in a sample, provided with the same or a differentformulation, may be administered to target different regions of the lungin one administration.

In order to relate the dispersion of powder at different inhalation flowrates, volumes, and from inhalers of different resistances, the energyrequired to perform the inhalation maneuver can be calculated.Inhalation energy can be calculated from the equation E=R²Q²V where E isthe inhalation energy in Joules, R is the inhaler resistance inkPa^(1/2)/LPM, Q is the steady flow rate in L/min and V is the inhaledair volume in L.

Healthy adult populations are predicted to be able to achieve inhalationenergies ranging from 2.9 to 22 Joules by using values of peakinspiratory flow rate (PIFR) measured by Clarke et al. (Journal ofAerosol Med, 6(2), p. 99-110, 1993) for the flow rate Q from two inhalerresistances of 0.02 and 0.055 kPa1/2/LPM, with a inhalation volume of 2L based on both FDA guidance documents for dry powder inhalers and onthe work of Tiddens et al. (Journal of Aerosol Med, 19, (4), p. 456-465,2006) who found adults averaging 2.2 L inhaled volume through a varietyof DPIs.

Dry powder particles can also be prepared using cone-jet mode ofelectrohydrodynamic atomization, as described by Li et al., ChemicalEngineering Science 61 (2006) 3091-3097. For example, an aspirinsolution flowing through a needle can be subjected to an electric fieldto generate droplets. The method is said to generating anear-monodispersed distribution of droplet relics, leading to formaspirin particulate crystals.

7. Methods of Treatment

In other aspects, the subject technology is a method for treating(including prophylactic treatment or reducing the risk) of acardiovascular disease (such as thrombosis), comprising administering tothe respiratory tract of a subject in need thereof an effective amountof respirable dry particles or dry powder, as described herein.

Cardiovascular diseases include, for example, atherosclerosis, coronaryartery disease (CAD), angina pectoris (commonly known as “angina”),thrombosis, ischemic heart disease, coronary insufficiency, peripheralvascular disease, myocardial infarction, cerebrovascular disease (suchas stroke), transient ischemic attack, arteriolosclerosis, small vesseldisease, elevated cholesterol, intermittent claudication orhypertension.

The respirable dry particles and dry powders can be administered to therespiratory tract of a subject in need thereof using any suitablemethod, such as instillation techniques, and/or an inhalation device,such as a dry powder inhaler (DPI) or metered dose inhaler (MDI). Anumber of DPIs are available, such as, the inhalers disclosed is U.S.Pat. Nos. 4,995,385 and 4,069,819, Spinhaler® (Fisons, Loughborough,U.K.), Rotahalers®, Diskhaler® and Diskus® (GlaxoSmithKline, ResearchTriangle Technology Park, North Carolina), FlowCapss®, TwinCaps®, XCaps(Hovione, Loures, Portugal), Inhalators® (Boehringer-Ingelheim,Germany), Aerolizer® (Novartis, Switzerland), and others known to thoseskilled in the art.

Generally, inhalation devices (e.g., DPIs) are able to deliver a maximumamount of dry powder or dry particles in a single inhalation, which isrelated to the capacity of the blisters, capsules (e.g. size 000, 00,0E, 0, 1, 2, 3, and 4, with respective volumetric capacities of 1.37 ml,950 μl, 770 μl, 680 μl, 480 μl, 360 μl, 270 μl, and 200 μl) or othermeans that contain the dry particles or dry powders within the inhaler.Accordingly, delivery of a desired dose or effective amount may requiretwo or more inhalations. Preferably, each dose that is administered to asubject in need thereof contains an effective amount of respirable dryparticles or dry powder and is administered using no more than about 4inhalations. For example, each dose of respirable dry particles or drypowder can be administered in a single inhalation or 2, 3, or 4inhalations. The respirable dry particles and dry powders, arepreferably administered in a single, breath-activated step using abreath-activated DPI. When this type of device is used, the energy ofthe subject's inhalation both disperses the respirable dry particles anddraws them into the respiratory tract.

The respirable dry particles or dry powders can be delivered byinhalation to a desired area within the respiratory tract, as desired.It is well-known that particles with an aerodynamic diameter of about 1micron to about 3 μm, can be delivered to the deep lung. Largeraerodynamic diameters, for example, from about 3 μm to about 5 μm can bedelivered to the central and upper airways.

For dry powder inhalers, oral cavity deposition is dominated by inertialimpaction and so characterized by the aerosol's Stokes number (DeHaan etal. Journal of Aerosol Science, 35 (3), 309-331, 2003). For equivalentinhaler geometry, breathing pattern and oral cavity geometry, the Stokesnumber, and so the oral cavity deposition, is primarily affected by theaerodynamic size of the inhaled powder. Hence, factors which contributeto oral deposition of a powder include the size distribution of theindividual particles and the dispersibility of the powder. If the MMADof the individual particles is too large, e.g. above 5 μm, then anincreasing percentage of powder will deposit in the oral cavity.Likewise, if a powder has poor dispersibility, it is an indication thatthe particles will leave the dry powder inhaler and enter the oralcavity as agglomerates. Agglomerated powder will perform aerodynamicallylike an individual particle as large as the agglomerate, therefore evenif the individual particles are small (e.g., MMAD of 5 μm or less), thesize distribution of the inhaled powder may have an MMAD of greater than5 μm, leading to enhanced oral cavity deposition.

Therefore, it is desirable to have a powder in which the particles aresmall (e.g., MMAD of 5 μm or less, e.g. between 1 to 5 μm), and arehighly dispersible (e.g. ¼ bar or alternatively, 0.5/4 bar of 2.0, andpreferably less than 1.5). More preferably, the respirable dry powder iscomprised of respirable dry particles with an MMAD between 1 to 4 μm or1 to 3 μm, and have a ¼ bar less than 1.4, or less than 1.3, and morepreferably less than 1.2.

The absolute geometric diameter of the particles measured at 1 bar usingthe HELOS system is not critical provided that the particle's envelopedensity is sufficient such that the MMAD is in one of the ranges listedabove, wherein MMAD is VMGD times the square root of the envelopedensity (MMAD=VMGD*sqrt(envelope density)). If it is desired to delivera high unit dose of salt using a fixed volume dosing container, then,particles of higher envelop density are desired. High envelope densityallows for more mass of powder to be contained within the fixed volumedosing container. Preferable envelope densities are greater than 0.1g/cc, greater than 0.25 g/cc, greater than 0.4 g/cc, greater than 0.5g/cc, and greater than 0.6 g/cc.

The respirable dry powders and particles of the subject technology canbe employed in compositions suitable for drug delivery via therespiratory system. For example, such compositions can include blends ofthe respirable dry particles of the subject technology and one or moreother dry particles or powders, such as dry particles or powders thatcontain another active agent, or that consist of or consist essentiallyof one or more pharmaceutically acceptable excipients.

Respirable dry powders and dry particles suitable for use in the methodsof the subject technology can travel through the upper airways (i.e.,the oropharynx and larynx), the lower airways, which include the tracheafollowed by bifurcations into the bronchi and bronchioli, and throughthe terminal bronchioli which in turn divide into respiratory bronchiolileading then to the ultimate respiratory zone, the alveoli or the deeplung. In one embodiment of the subject technology, most of the mass ofrespirable dry powders or particles deposit in the deep lung. In anotherembodiment of the subject technology, delivery is primarily to thecentral airways. In another embodiment, delivery is to the upperairways.

The respirable dry particles or dry powders of the subject technologycan be delivered by inhalation at various parts of the breathing cycle(e.g., laminar flow at mid-breath). An advantage of the highdispersibility of the dry powders and dry particles of the subjecttechnology is the ability to target deposition in the respiratory tract.For example, breath controlled delivery of nebulized solutions is arecent development in liquid aerosol delivery (Dalby et al. inInhalation Aerosols, edited by Hickey 2007, p. 437). In this case,nebulized droplets are released only during certain portions of thebreathing cycle. For deep lung delivery, droplets are released in thebeginning of the inhalation cycle, while for central airway deposition,they they are released later in the inhalation.

The dry powders of this subject technology provide advantages fortargeting the timing of drug delivery in the breathing cycle and alsolocation in the human lung. Because the respirable dry powders of thesubject technology can be dispersed rapidly, such as within a fractionof a typical inhalation maneuver, the timing of the powder dispersal canbe controlled to deliver an aerosol at specific times within theinhalation.

With a highly dispersible powder, the complete dose of aerosol can bedispersed at the beginning portion of the inhalation. While thepatient's inhalation flow rate ramps up to the peak inspiratory flowrate, a highly dispersible powder will begin to disperse already at thebeginning of the ramp up and could completely disperse a dose in thefirst portion of the inhalation. Since the air that is inhaled at thebeginning of the inhalation will ventilate deepest into the lungs,dispersing the most aerosol into the first part of the inhalation ispreferable for deep lung deposition. Similarly, for central deposition,dispersing the aerosol at a high concentration into the air which willventilate the central airways can be achieved by rapid dispersion of thedose near the mid to end of the inhalation. This can be accomplished bya number of mechanical and other means such as a switch operated bytime, pressure or flow rate which diverts the patient's inhaled air tothe powder to be dispersed only after the switch conditions are met.

Aerosol dosage, formulations and delivery systems may be selected for aparticular therapeutic application, as described, for example, in Gonda,I. “Aerosols for delivery of therapeutic and diagnostic agents to therespiratory tract,” in Critical Reviews in Therapeutic Drug CarrierSystems, 6: 273-313 (1990); and in Moren, “Aerosol Dosage Forms andFormulations,” in Aerosols in Medicine, Principles, Diagnosis andTherapy, Moren, et al., Eds., Esevier, Amsterdam (1985).

Suitable intervals between doses that provide the desired therapeuticeffect can be determined based on the severity of the condition, overallwell being of the subject and the subject's tolerance to respirable dryparticles and dry powders and other considerations. Based on these andother considerations, a clinician can determine appropriate intervalsbetween doses. Generally, respirable dry particles and dry powders areadministered once, twice or three times a day, as needed.

In some embodiments the amount of NSAID delivered to the respiratorytract (e.g., lungs, respiratory airway) is about 0.001 mg/kg bodyweight/dose to about 2 mg/kg body weight/dose, about 0.002 mg/kg bodyweight/dose to about 2 mg/kg body weight/dose, about 0.005 mg/kg bodyweight/dose to about 2 mg/kg body weight/dose, about 0.01 mg/kg bodyweight/dose to about 2 mg/kg body weight/dose, about 0.02 mg/kg bodyweight/dose to about 2 mg/kg body weight/dose, about 0.05 mg/kg bodyweight/dose to about 2 mg/kg body weight/dose, about 0.075 mg/kg bodyweight/dose to about 2 mg/kg body weight/dose, about 0.1 mg/kg bodyweight/dose to about 2 mg/kg body weight/dose, about 0.2 mg/kg bodyweight/dose to about 2 mg/kg body weight/dose, about 0.5 mg/kg bodyweight/dose to about 2 mg/kg body weight/dose, or about 0.75 mg/kg bodyweight/dose to about 2 mg/kg body weight/dose.

In certain embodiments, at least about 50%, at least about 60%, at leastabout 70%, at least about 75%, at least about 80%, at least about 85%,at least about 90%, at least about 95%, or at least about 99%, of theadministered acetylsalicylic acid reaches the systemic circulation of asubject within about 60 minutes upon administration, or within about 40minutes upon administration, or within about 30 minutes uponadministration, or within about 20 minutes upon administration, orwithin about 15 minutes upon administration.

In certain embodiments, the method and delivery devices described hereincan deliver acetylsalicylic acid, and pharmacologically active metabolicbyproducts of acetylsalicylic acid thereof, to the systemic circulation,at levels that are substantially the same, or higher as compared tothose delivered by oral administration of about 30 mg of acetylsalicylicacid.

In certain embodiments, the method and delivery devices described hereincan deliver acetylsalicylic acid, and pharmacologically active metabolicbyproducts of acetylsalicylic acid thereof, to the systemic circulation,at levels that are substantially the same, or higher as compared tothose delivered by oral administration of about 40 mg of acetylsalicylicacid.

In certain embodiments, the method and delivery devices described hereincan deliver acetylsalicylic acid, and pharmacologically active metabolicbyproducts of acetylsalicylic acid thereof, to the systemic circulation,at levels that are substantially the same, or higher as compared tothose delivered by oral administration of about 50 mg of acetylsalicylicacid.

In certain embodiments, the method and delivery devices described hereincan deliver acetylsalicylic acid, and pharmacologically active metabolicbyproducts of acetylsalicylic acid thereof, to the systemic circulation,at levels that are substantially the same, or higher as compared tothose delivered by oral administration of about 80 mg of acetylsalicylicacid.

In certain embodiments, the method and delivery devices described hereincan deliver acetylsalicylic acid, and pharmacologically active metabolicbyproducts of acetylsalicylic acid thereof, to the systemic circulation,at levels that are substantially the same, or higher as compared tothose delivered by oral administration of about 162 mg ofacetylsalicylic acid.

The doses of acetylsalicylic acid administered in order to achieve alevel (or an average level among a population of patients) that issubstantially the same, or higher as compared to those delivered by oraladministration of about 30 mg, about 40 mg, about 50 mg, about 80 mg, orabout 182 mg of acetylsalicylic acid can be determined by conventionalmethods. The dosing, administration techniques and schedules are knownin the art are within the ability of the skilled clinician. For example,the serum level of acetylsalicylic acid, or a metabolite thereof, in asubject (or average serum level among a population of subjects) can bedetermined by convention pharmacokinetic or pharmacodynamics studies.

In certain embodiments, the method and delivery devices described hereincan deliver acetylsalicylic acid to the systemic circulation such thatcirculating plasma level of acetylsalicylic acid is at least about 1mcg/mL, at least about 2 mcg/mL, at least about 3 mcg/mL, at least about4 mcg/mL, at least about 5 mcg/mL, or at least about 6 mcg/mL withinabout 60 minutes upon administration, or within about 40 minutes uponadministration, or within about 30 minutes upon administration, orwithin about 20 minutes upon administration, or within about 15 minutesupon administration.

In certain embodiments, the method and delivery devices described hereincan deliver acetylsalicylic acid to the systemic circulation such thatcirculating plasma level of salicylate is about 8 mcg/mL, about 9mcg/mL, about 10 mcg/mL, about 11 mcg/mL, about 12 mcg/mL, about 15mcg/mL, within about 60 minutes upon administration, or within about 40minutes upon administration, or within about 30 minutes uponadministration, or within about 20 minutes upon administration, orwithin about 15 minutes upon administration.

If desired or indicated, the respirable dry particles and dry powdersdescribed herein can be administered with one or more other therapeuticagents. The other therapeutic agents can be administered by any suitableroute, such as orally, parenterally (e.g., intravenous, intraarterial,intramuscular, or subcutaneous injection), topically, by inhalation(e.g., intrabronchial, intranasal or oral inhalation, intranasal drops),rectally, vaginally, and the like. The respirable dry particles and drypowders can be administered before, substantially concurrently with, orsubsequent to administration of the other therapeutic agent. Preferably,the respirable dry particles and dry powders and the other therapeuticagent are administered so as to provide substantial overlap of theirpharmacologic activities.

The foregoing description is provided to enable a person skilled in theart to practice the various configurations described herein. While thesubject technology has been particularly described with reference to thevarious figures and configurations, it should be understood that theseare for illustration purposes only and should not be taken as limitingthe scope of the subject technology.

There may be many other ways to implement the subject technology.Various functions and elements described herein may be partitioneddifferently from those shown without departing from the scope of thesubject technology. Various modifications to these configurations willbe readily apparent to those skilled in the art, and generic principlesdefined herein may be applied to other configurations. Thus, manychanges and modifications may be made to the subject technology, by onehaving ordinary skill in the art, without departing from the scope ofthe subject technology.

It is understood that the specific order or hierarchy of steps in theprocesses disclosed is an illustration of exemplary approaches. Basedupon design preferences, it is understood that the specific order orhierarchy of steps in the processes may be rearranged. Some of the stepsmay be performed simultaneously. The accompanying method claims presentelements of the various steps in a sample order, and are not meant to belimited to the specific order or hierarchy presented.

As used herein, the phrase “at least one of” preceding a series ofitems, with the term “and” or “or” to separate any of the items,modifies the list as a whole, rather than each member of the list (i.e.,each item). The phrase “at least one of” does not require selection ofat least one of each item listed; rather, the phrase allows a meaningthat includes at least one of any one of the items, and/or at least oneof any combination of the items, and/or at least one of each of theitems. By way of example, the phrases “at least one of A, B, and C” or“at least one of A, B, or C” each refer to only A, only B, or only C;any combination of A, B, and C; and/or at least one of each of A, B, andC.

Furthermore, to the extent that the term “include,” “have,” or the likeis used in the description or the claims, such term is intended to beinclusive in a manner similar to the term “comprise” as “comprise” isinterpreted when employed as a transitional word in a claim.

The word “exemplary” is used herein to mean “serving as an example,instance, or illustration.” Any embodiment described herein as“exemplary” is not necessarily to be construed as preferred oradvantageous over other embodiments.

A reference to an element in the singular is not intended to mean “oneand only one” unless specifically stated, but rather “one or more.”Pronouns in the masculine (e.g., his) include the feminine and neutergender (e.g., her and its) and vice versa. The term “some” refers to oneor more. Underlined and/or italicized headings and subheadings are usedfor convenience only, do not limit the subject technology, and are notreferred to in connection with the interpretation of the description ofthe subject technology. All structural and functional equivalents to theelements of the various configurations described throughout thisdisclosure that are known or later come to be known to those of ordinaryskill in the art are expressly incorporated herein by reference andintended to be encompassed by the subject technology. Moreover, nothingdisclosed herein is intended to be dedicated to the public regardless ofwhether such disclosure is explicitly recited in the above description.

It is to be understood that, while the subject technology has beendescribed in conjunction with the detailed description, thereof, theforegoing description is intended to illustrate and not limit the scopeof the subject technology. Other aspects, advantages, and modificationsof the subject technology are within the scope of the claims set forthbelow. The specification is most thoroughly understood in light of theteachings of the references cited within the specification. Theembodiments within the specification provide an illustration ofembodiments of the invention and should not be construed to limit thescope of the invention. The skilled artisan readily recognizes that manyother embodiments are encompassed by the invention. All publications andpatents cited in this disclosure are incorporated by reference in theirentirety. To the extent the material incorporated by referencecontradicts or is inconsistent with this specification, thespecification will supersede any such material. The citation of anyreferences herein is not an admission that such references are prior artto the present invention.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following embodiments.

What is claimed is:
 1. A method of treating thrombosis or reducing risk of a thromboembolic event in a subject in need thereof, the method comprising administering by pulmonary delivery to the subject dry particles free of excipients from within a dry powder inhaler, wherein the dry particles in the inhaler before the administering are provided in a capsule or blister and consist of acetylsalicylic acid or a pharmaceutically acceptable salt thereof, wherein the dry particles have a mass median aerodynamic diameter (MMAD) of less than 5 μm, and wherein the dry particles deliver at least 50% of administered acetylsalicylic acid to systemic circulation of the subject with about 15 minutes after the administering.
 2. The method of claim 1, wherein the dry powder formulation delivers at least 60% of administered acetylsalicylic acid to systemic circulation of the subject within about 15 minutes of administration.
 3. The method of claim 1, wherein the dry powder formulation delivers at least 70% of administered acetylsalicylic acid to systemic circulation of the subject within about 15 minutes of administration.
 4. The method of claim 1, wherein the dry powder formulation delivers at least 80% of administered acetylsalicylic acid to systemic circulation of the subject within about 15 minutes of administration.
 5. The method of claim 1, wherein the dose of acetylsalicylic acid administered to the subject is about 40 mg or less.
 6. The method of claim 5, wherein the dose of acetylsalicylic acid administered to the subject is about 30 mg or less.
 7. A method of treating thrombosis or reducing risk of a thromboembolic event in a subject in need thereof, the method comprising administering by pulmonary delivery to the subject dry particles free of excipients from within a dry powder inhaler, wherein the dry particles in the inhaler before the administering are provided in a capsule or blister and consist of acetylsalicylic acid or a pharmaceutically acceptable salt thereof, wherein the dry particles have a geometric diameter (VMGD) of less than 5 μm, and wherein the dry particles deliver at least 50% of administered acetylsalicylic acid to systemic circulation of the subject with about 15 minutes after the administering.
 8. The method of claim 7, wherein the dry powder formulation delivers at least 60% of administered acetylsalicylic acid to systemic circulation of the subject within about 15 minutes of administration.
 9. The method of claim 7, wherein the dry powder formulation delivers at least 70% of administered acetylsalicylic acid to systemic circulation of the subject within about 15 minutes of administration.
 10. The method of claim 7, wherein the dry powder formulation delivers at least 80% of administered acetylsalicylic acid to systemic circulation of the subject within about 15 minutes of administration.
 11. The method of claim 7, wherein the dose of acetylsalicylic acid administered to the subject is about 40 mg or less.
 12. The method of claim 11, wherein the dose of acetylsalicylic acid administered to the subject is about 30 mg or less. 